Process for preparing antiviral compounds

ABSTRACT

This disclosure is directed to: (a) processes for preparing compounds and salts thereof that, inter alia, are useful for inhibiting hepatitis C virus (HCV); (b) intermediates useful for the preparation of the compounds and salts; (c) pharmaceutical compositions comprising the compounds or salts; and (d) methods of use of such compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.13/184,440, filed Jul. 15, 2011, which claims priority to U.S.Provisional Application No. 61/444,475 filed Feb. 18, 2011 and U.S.Provisional Application No. 61/365,293 filed Jul. 16, 2010, the entirecontents of which are incorporated herein by reference.

TECHNICAL FIELD

This disclosure is directed to: (a) processes for preparing a compoundand salts thereof that, inter alia, are useful for inhibiting hepatitisC virus (HCV); (b) intermediates useful for the preparation of thecompound and salts; (c) pharmaceutical compositions comprising thecompound or salts; and (d) methods of use of such compositions.

BACKGROUND

Hepatitis C is a blood-borne, infectious, viral disease that is causedby a hepatotropic virus called HCV. At least six different HCV genotypes(with several subtypes within each genotype) are known to date. In NorthAmerica, HCV genotype 1a predominates, followed by HCV genotypes 1b, 2a,2b, and 3a. In the United States, HCV genotypes 1, 2, and 3 are the mostcommon, with about 80% of the hepatitis C patients having HCVgenotype 1. In Europe, HCV genotype 1 b is predominant, followed by HCVgenotypes 2a, 2b, 2c, and 3a. HCV genotypes 4 and 5 are found almostexclusively in Africa. As discussed below, the patient's HCV genotype isclinically important in determining the patient's potential response totherapy and the required duration of such therapy.

An HCV infection can cause liver inflammation (hepatitis) that is oftenasymptomatic, but ensuing chronic hepatitis can result in cirrhosis ofthe liver (fibrotic scarring of the liver), liver cancer, and/or liverfailure. The World Health Organization estimates that about 170 millionpersons worldwide are chronically infected with HCV, and from aboutthree to about four million persons are newly infected globally eachyear. According to the Centers for Disease Control and Prevention, aboutfour million people in the United States are infected with HCV.Co-infection with the human immunodeficiency virus (HIV) is common, andrates of HCV infection among HIV positive populations are higher.

There is a small chance of clearing the virus spontaneously, but themajority of patients with chronic hepatitis C will not clear it withouttreatment. Indications for treatment typically include proven HCVinfection and persistent abnormal liver function tests. There are twotreatment regimens that are primarily used to treat hepatitis C:monotherapy (using an interferon agent—either a “conventional” orlonger-acting pegylated interferon) and combination therapy (using aninterferon agent and ribavirin). Interferon, which is injected into thebloodstream, works by bolstering the immune response to HCV; andribavirin, which is taken orally, is believed to work by preventing HCVreplication. Taken alone, ribavirin does not effectively suppress HCVlevels, but an interferon/ribavirin combination is more effective thaninterferon alone. Typically, hepatitis C is treated with a combinationof pegylated interferon alpha and ribavirin for a period of 24 or 48weeks, depending on the HCV genotype.

The goal of treatment is sustained viral response—meaning that HCV isnot measurable in the blood after therapy is completed.

Treatment may be physically demanding, particularly for those with priorhistory of drug or alcohol abuse, because both interferon and ribavirinhave numerous side effects. Common interferon-associated side effectsinclude flu-like symptoms, extreme fatigue, nausea, loss of appetite,thyroid problems, high blood sugar, hair loss, and skin reactions at theinjection site. Possible serious interferon-associated side effectsinclude psychoses (e.g., suicidal behavior), heart problems (e.g., heartattack, low blood pressure), other internal organ damage, blood problems(e.g., blood counts falling dangerously low), and new or worseningautoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associatedside effects include anemia, fatigue, irritability, skin rash, nasalstuffiness, sinusitis, and cough. Ribavirin can also cause birthdefects, so pregnancy in female patients and female partners of malepatients must be avoided during treatment and for six months afterward.

Some patients do not complete treatment because of the serious sideeffects discussed above; other patients (non-responders) continue tohave measurable HCV levels despite treatment; and yet other patients(relapsers) appear to clear the virus during therapy, but the virusreturns sometime after completion of the treatment regimen. Thus, therecontinues to be a need for alternative compositions and methods oftreatment (used either in combination with, or in lieu of, an interferonagent and/or ribavirin) to prevent the progression of liver damage fromhepatitis C.

SUMMARY

This disclosure is directed to processes for preparing compounds offormula (A)

This disclosure is also directed to processes for preparing compoundssuch asN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(compound (A-1)) or a salt thereof, wherein the process comprisessulfonamidation of a sulfonate (compound (5)).

This disclosure also is directed to compound (A) and salts thereofprepared by the processes described herein.

This disclosure also is directed to compound (A) and potassium or sodiumsalts thereof prepared by the processes described herein.

This disclosure also is directed to a process for preparing compound(5).

This disclosure also is directed to compound (4).

This disclosure also is directed to various intermediates useful forpreparing compound (4) as well as to processes for preparing thoseintermediates.

This disclosure also is directed to intermediate compounds (1) and (3)useful for preparing compound (4) as well as to processes for preparingthose intermediates.

This disclosure also is directed to compositions (includingpharmaceutical compositions) that comprise compound (A) or salt thereofthat are prepared by the above processes. Optionally, the compositionscan comprise one or more additional therapeutic agents.

This disclosure also is directed to methods of use of the abovecompounds and compositions to, for example, inhibit replication of aribonucleic acid (RNA) virus (including HCV) or treat a diseasetreatable by inhibiting HCV RNA polymerase (including hepatitis C).

Further benefits of this disclosure will be apparent to one skilled inthe art.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the effect of air and sodium ascorbate on an exemplarycoupling reaction.

DETAILED DESCRIPTION

This detailed description is intended only to acquaint others skilled inthe art with this disclosure, its principles, and its practicalapplication so that others skilled in the art may adapt and apply thedisclosure in its numerous forms, as they may be best suited to therequirements of a particular use. This description and its specificexamples are intended for purposes of illustration only. Thisdisclosure, therefore, is not limited to the embodiments described inthis patent application, and may be variously modified.

This disclosure is directed, in part, to processes for preparingcompounds of formula (A) such asN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(compound (A-1)) or a salt thereof. The salt of compound (A) may be thepotassium salt, the sodium salt or any other suitable salt. Inembodiments, the salt of compound (A) is the potassium salt. Inembodiments, the salt of compound (A) is the sodium salt.

The process comprises sulfonamidation of compound (5), wherein LG¹ is aleaving group; R⁴ is selected from the group consisting of C₁-C₆-alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-hydroxyalkyl, phenyl, 2-thienyl, 3-thienyl,2-furanyl, and 3-furanyl; R⁵ is selected from the group consisting ofhydrogen, fluoro, chloro, C₁-C₆-alkyl, and C₁-C₆-alkyloxy; and R⁶ isselected from the group consisting of C₁-C₆-alkyl and C₁-C₆-fluoroalkyl.

In embodiments, LG¹ is selected from the group consisting of chloro,bromo, iodo and —OSO₂R^(1a), wherein R^(1a) is selected from the groupconsisting of aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl,—N(alkyl)₂, —O(alkyl), —O(aryl), fluoro, imidazolyl, and isomers andhomologs thereof.

In embodiments, LG¹ is —OSO₂R^(1a), wherein R^(1a) is aryl, such asp-tolyl or phenyl; alkyl such as methyl or ethyl; fluoroalkyl such astrifluoromethyl, perfluorobutyl (C₄F₉), or isomers of perfluorobutyl andother higher and lower homologs such as, but not limited to,perfluoropentyl, perfluorohexyl, and perfluorooctyl. In embodiments,R^(1a) is -fluoroalkyl-O-fluoroalkyl such as perfluoroethoxyethyl;—N(alkyl)₂; fluoro; or imidazolyl.

Process for Preparing Compounds of Formula (A) such asN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1)) and the Corresponding Salt

In an embodiment, the process comprises sulfonamidation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylnonafluorobutane-1-sulfonate (compound (5-1)) selected from the groupconsisting of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate,6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,1,2,3,3,4,4,4-nonafluorobutane-2-sulfonate,6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propane-1-sulfonate, and6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane-2-sulfonate.

In an embodiment, the process comprises sulfonamidation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (compound (5a)).

Compound (5) may be sulfonamidated using a transition metal catalyst ora transition metal catalyst precursor and ligand.

In embodiments, the ligand has a structure corresponding to thestructure of formula (I),

wherein X is a cyclic or acyclic phosphine.

Ar¹ and Ar² are each independently aryl or heteroaryl. Examples of theAr¹-Ar² group are given in formulae (I-1)-(I-42)

wherein X is a phosphine;V¹, V², V³, and V⁴ are independently selected from CR¹ or N;V⁵, V⁶, V⁷, V⁸ and V⁹ are independently selected from CR² or N;W¹, W², and W³ are independently selected from CR¹, NR¹, N or O;W⁴ is C or N;W⁵ is C or N;W⁶, W⁷, W⁸ and W⁹ are independently selected from CR², NR², N or O; andring C, at each occurrence, is independently a fused-aryl orfused-heteroaryl unsubstituted or substituted with R¹ and R²,respectively, any number of times depending on, for example, stabilityand rules of valence.

indicates that the 5- or 6-membered ring is aromatic.

Ar¹ and Ar² are each independently optionally substituted with groupssuch as one or more R¹ and R², respectively. Ar¹ and Ar² independentlymay be substituted with R¹ and R², respectively, any number of timesdepending on, for example, stability and rules of valence. The absenceof an R group in any of the formulae (I-1)-(I-42) indicates in theconventional way that the position is occupied by a hydrogen atom.

In embodiments, R¹ and R² are independently selected at each occurrencefrom the group consisting of hydrogen; amino; hydroxyl; cyano; halo;alkyl; alkenyl; alkynyl; haloalkyl; haloalkoxy; oxoalkyl; alkoxy;alkylamino; dialkylamino; cycloalkyl optionally substituted with groupssuch as alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl orhaloalkoxy; cycloalkyloxy optionally substituted with groups such asalkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;5- or 6-membered heteroaryl optionally substituted with groups such asalkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;phenyl optionally substituted with groups such as alkyl, alkenyl,alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; hydroxyalkyl;hydroxyalkoxy; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl;N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl; L¹-C(O)—OR^(1′),L¹-P(O)—(OR^(1′))₂, or L¹-S(O)₂—OR^(1′), wherein L¹ is a bond oralkylene, and R^(1′) is selected from the group consisting of hydrogen,alkyl and hydroxyalkyl; L²-O—C(O)—R^(2′), wherein L² is a bond oralkylene, and R^(2′) is alkyl or hydroxyalkyl; L³-C(O)—NR^(3′)R^(4′),wherein is a bond or alkylene, and R^(3′) and R^(4′) are eachindependently selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl; L⁴-NR^(5′)—C(O)—R^(6′), wherein L⁴ is a bond or alkylene,R^(5′) is hydrogen or alkyl, and R^(6′) is alkyl or hydroxyalkyl;sulfamoyl; N-(alkyl)sulfamoyl; N,N-(dialkyl)sulfamoyl; sulfonamide;sulfate; alkylthio; and thioalkyl; or an R¹ and an R² join together toform an alkylene or —O—(CH₂)_(m)—O—, wherein m is 1, 2, 3 or 4.

In embodiments, each of R¹ and R² substituted as shown in each offormulae (I-1)-(I-42) are independently alkyl, alkoxy, dialkylamino,haloalkyl, fluoroalkyl, or phenyl. In embodiments, the alkyl groups areC₁-C₃ alkyl, the alkoxy groups are C₁-C₃ alkoxy, and the alkyl groups ofhaloalkyl and fluoroalkyl are C₁-C₃ alkyl. Examples of alkyls includemethyl, ethyl, and isopropyl. Examples of alkoxys include methoxy andisopropoxy. An example of a haloalkyl includes trifluoromethyl. Anexample of a dialkylamino includes dimethylamino.

In embodiments, X is a phosphorous containing heterocyclic ring ofFormula (Ia).

In these ligands, a phosphorus heterocycle labeled above as ring A (a“phosphacycle”) is bonded through a phosphorus atom to a substitutedaromatic ring that is, in turn, substituted with another aromatic ringat an adjacent or ortho carbon atom to the phosphacycle. Thephosphacycle contains three or more ring atoms including a phosphorusatom and two ring carbons bonded directly to the phosphorus atom. Ring Amay be a phosphorus monocyclic heterocyclic ring, a bicyclicheterocyclic ring, or a tricyclic heterocyclic ring. Ring A includes 0to 9 ring atoms in addition to the phosphorus and 2 carbon ring atoms offormula (Ia). Each of the ring atoms may be independently selected fromthe group consisting of carbon, oxygen, nitrogen and sulfur. The tworing carbons bonded to the phosphorus atom may be bonded to substituentsR¹⁰, R¹¹, R¹², and R¹³ through a carbon atom, i.e., substituents R¹⁰,R¹¹, R¹², and R¹³ may be bonded to the phosphacycle through a carbonatom of the respective substituents. The phosphacycle may optionallycontain one or more ring substituents selected from the group consistingof alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylthio; alkynyl;aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl;N,N,N-trialkylammoniumalkyl; arylalkyl optionally substituted withgroups such as alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkylor haloalkoxy; cycloalkyl optionally substituted with groups such asalkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;dialkylamino; halo; haloalkyl; fluoroalkyl; M₅-M₆heteroaryl optionallysubstituted with groups such as alkyl, alkenyl, alkynyl, alkoxy, cyano,halo, haloalkyl or haloalkoxy; heterocycloalkyl optionally substitutedwith groups such as alkyl, alkenyl, alkynyl, alkoxy, cyano, halo,haloalkyl or haloalkoxy; hydroxy; hydroxyalkyl; oxo; an exocyclic doublebond optionally substituted with groups such as alkyl, alkenyl, alkynyl,aryl, cycloalkyl, heterocyclyl, or heteroaryl; a 3- to 7-membered Spiroring containing zero, one, or two heteroatoms; phenyl optionallysubstituted with groups such as alkyl, alkenyl, alkynyl, alkoxy, cyano,halo, haloalkyl or haloalkoxy; L¹-C(O)—OR^(1′), L¹-P(O)—(OR^(1′))₂, orL¹-S(O)₂—OR^(1′), wherein L¹ is a bond or alkylene, and R^(1′) isselected from the group consisting of hydrogen, alkyl and hydroxyalkyl;L²-O—C(O)—R^(2′), wherein L² is a bond or alkylene, and R^(2′) is alkylor hydroxyalkyl; L³-C(O)—NR^(3′)R^(4′), wherein L³ is a bond oralkylene, and R^(3′) and R^(4′) are each independently selected from thegroup consisting of hydrogen, alkyl, and hydroxyalkyl;L⁴-NR^(5′)—C(O)—R^(6′), wherein L⁴ is a bond or alkylene, R^(5′) ishydrogen or alkyl, and R^(6′) is alkyl or hydroxyalkyl; andL⁷-NR^(8′)—S(O)₂—R^(9′), wherein L⁷ is a bond or alkylene, R^(8′) ishydrogen or alkyl, and R^(9′) is alkyl or hydroxyalkyl.

In various embodiments, ring A is a 4-, 5-, 6-, 7-, or 8-membered ringcontaining no hetero ring atoms except the P-atom shown in Formula (Ia).Ring A may be a single ring containing no bridging atoms, or ring A maybe a polycyclic ring such as a bicyclic or tricyclic ring containingbridging atoms.

In embodiments, R¹⁰, R¹¹, R¹², and R¹³ may each be independentlyselected from the group consisting of hydrogen; alkyl; alkenyl;haloalkyl; alkynyl; oxoalkyl; cycloalkyl optionally substituted withalkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;heterocyclyl optionally substituted with groups such as alkyl, alkenyl,alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; M₅-M₆heteroaryloptionally substituted with groups such as alkyl, alkenyl, alkynyl,alkoxy, cyano, halo, haloalkyl or haloalkoxy; phenyl optionallysubstituted with groups such as alkyl, alkenyl, alkynyl, alkoxy, cyano,halo, haloalkyl or haloalkoxy; hydroxyalkyl; alkoxyalkyl; aminoalkyl;N-alkylaminoalkyl; N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl;thioalkyl; L¹³-C(O)—OR^(14′), L¹³-P(O)—(OR^(14′))₂, orL¹³-S(O)₂—OR^(14′), wherein L¹³ is a bond or alkylene, and R^(14′) isselected from the group consisting of hydrogen, alkyl and hydroxyalkyl;L¹⁵-O—C(O)—R^(16′), wherein L¹⁵ is alkylene and R^(16′) is alkyl orhydroxyalkyl; L¹⁷-C(O)—NR^(18′)R^(19′), wherein L¹⁷ is a bond oralkylene, and R^(18′) and R^(19′) are each independently selected fromthe group consisting of hydrogen, alkyl, and hydroxyalkyl; andL²⁰-NR^(21′)—C(O)—R^(22′), wherein L²⁰ is alkylene, R^(21′) is hydrogenor alkyl, and R^(22′) is alkyl or hydroxyalkyl.

In addition to the substituents defined above for R¹⁰, R¹¹, R¹², andR¹³, or alternatively, each of R¹⁰, R¹¹, R¹², and R¹³ may independentlybe involved in forming a ring. For example, R¹⁰ or R¹¹ together with R¹²or R¹³ may form a ring. R¹⁰ and R¹¹ together with the carbon atom towhich they are attached may form a spirocyclic ring and/or R¹² and R¹³together with the carbon atom to which they are attached may form aspirocyclic ring. One or more of R¹⁰, R¹¹, R¹² and R¹³ may form a ringtogether with a ring substituent of ring A.

In embodiments, X is a phosphorous containing heterocyclic ring ofFormula (Ib).

Phosphacycles of formula Ib are bonded through a phosphorus atom to anoptionally substituted aromatic ring that is, in turn, substituted withanother aromatic ring at an adjacent or ortho carbon atom to thephosphorus atom. The phosphacycle contains a ferrocenyl moiety inaddition to a phosphorus atom and two ring carbons bonded directly tothe phosphorus atom. The two ring carbons bonded to the phosphorus atomare in turn bonded to substituents R¹⁰, R¹¹, R¹², and R¹³ through acarbon atom, i.e., substituents R¹⁰, R¹¹, R¹², and R¹³ are bonded to thephosphacycle through a carbon atom of the respective substituents. R¹⁰,R¹¹, R¹², and R¹³ are as described above.

In embodiments, X is fused to Ar¹ to give a compound of formula (Ic):

Ring B is a phosphorus heterocyclic ring (phosphacycle) with 0 to 5 ringatoms in addition to the phosphorus and carbon ring atom of formula(Ic). Each of the ring atoms may be independently selected from thegroup consisting of carbon, oxygen, nitrogen and sulfur. Thephosphacycle may also optionally contain one or more ring substituentsselected from the group consisting of alkenyl; alkoxy; alkoxyalkyl;alkyl; alkylamino; alkylthio; alkynyl; aminoalkyl; N-alkylaminoalkyl;N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl; arylalkyl optionallysubstituted with groups such as alkyl, alkenyl, alkynyl, alkoxy, cyano,halo, haloalkyl or haloalkoxy; cycloalkyl optionally substituted withgroups such as alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkylor haloalkoxy; dialkylamino; halo; haloalkyl; fluoroalkyl;M₅-M₆heteroaryl optionally substituted with groups such as alkyl,alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;heterocycloalkyl optionally substituted with groups such as alkyl,alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; hydroxy;hydroxyalkyl; oxo; an exocyclic double bond optionally substituted withgroups such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,or heteroaryl; a 3- to 7-membered spiro ring containing zero, one, ortwo heteroatoms; phenyl optionally substituted with groups such asalkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;L¹-C(O)—OR^(1′), L¹-P(O)—(OR^(1′))₂, or L¹-S(O)₂—OR^(1′), wherein L¹ isa bond or alkylene, and R^(1′) is selected from the group consisting ofhydrogen, alkyl or hydroxyalkyl; L²-O—C(O)—R^(2′), wherein L² is a bondor alkylene, and R^(2′) is alkyl or hydroxyalkyl; L³-C(O)—NR^(3′)R^(4′),wherein L³ is a bond or alkylene, and R^(3′) and R^(4′) are eachindependently selected from the group consisting of hydrogen, alkyl, andhydroxyalkyl; L⁴-NR^(5′)—C(O)—R^(6′), wherein L⁴ is a bond or alkylene,R^(5′) is hydrogen or alkyl, and R^(6′) is alkyl or hydroxyalkyl; andL⁷-NR^(8′)—S(O)₂—R^(9′), wherein L⁷ is a bond or alkylene, R^(8′) ishydrogen or alkyl, and R^(9′) is alkyl or hydroxyalkyl.

R¹⁴ and R¹⁵, together with the carbon atom to which they are attached,may form a spirocyclic ring. One or more of R¹⁴ and R¹⁵ may form a ringtogether with a ring substituent of ring B. Each of R¹⁴ and R¹⁵ may beindependently selected from the group consisting of hydrogen; alkyl;alkenyl; haloalkyl; alkynyl; oxoalkyl; cycloalkyl optionally substitutedwith groups such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, or heteroaryl; heterocyclyl optionally substituted withgroups such as alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkylor haloalkoxy; M₅-M₆heteroaryl optionally substituted with groups suchas alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl orhaloalkoxy; phenyl optionally substituted with groups such as alkyl,alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy;hydroxyalkyl; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl;N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl; thioalkyl;L¹³-C(O)—OR^(14′), L¹³-P(O)—(OR^(14′))₂, or L¹³-S(O)₂—OR^(14′) whereinL¹³ is a bond or alkylene, and R^(14′) is selected from the groupconsisting of hydrogen, alkyl and hydroxyalkyl; L¹⁵-O—C(O)—R^(16′)wherein L¹⁵ is alkylene, and R^(16′) is alkyl or hydroxyalkyl;L¹⁷-C(O)—NR^(18′)R^(19′), wherein L¹⁷ is a bond or alkylene and R^(18′)and R^(19′) are each independently selected from the group consisting ofhydrogen, alkyl, and hydroxyalkyl; and L²⁰-NR^(21′)—C(O)—R^(22′),wherein L²⁰ is alkylene, R^(21′) is hydrogen or alkyl, and R^(22′) isalkyl or hydroxyalkyl.

R^(P) may be selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl. R^(P) may beselected from the group consisting of alkylene, alkenylene, alkynylene,or —(CR⁴¹R⁴²—O)_(q)— wherein one end is attached to the phosphorus atomof the phosphacycle and the other end is attached to a B ring atom,wherein R⁴¹ and R⁴² are each independently hydrogen or alkyl, andwherein q is 1 or 2. In other words, when R^(P) is alkylene, alkenylene,alkynylene, or —(CR⁴¹R⁴²—O)^(q)—, R^(P) may be a bridging group betweenthe phosphorous atom of the phosphacycle and another ring atom of ringB.

In embodiments, the phosphacycle X has a structure corresponding to thestructure of formula (Id):

where the groups R¹⁰, R¹¹, R¹², and R¹³ are as described above. Thephosphacycle of formula (Id) is a six-membered ring, wherein bonds a andb are single bonds or double bonds, provided that a and b are notsimultaneously double bonds.

represents a bond that is either a single or double bond.

In the phosphacycles of formula (Id), one or more of the substituentsR¹⁶, R¹⁷, R¹⁸, and R¹⁹ may optionally form a ring with substituents R¹⁰,R¹¹, R¹², or R¹³. In addition to, or alternatively, R¹⁶ and R¹⁹ may beindependently selected from hydrogen halo, alkyl, haloalkyl,fluoroalkyl, alkenyl, and alkoxy. In embodiments, each of R¹⁶ and R¹⁹ ishydrogen.

R¹⁷ and R¹⁸ together with the carbon atom to which they are attached mayform a carbonyl; an exocyclic double bond optionally substituted withgroups such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,or heteroaryl; or a 3- to 7-membered spiro ring containing zero, one, ortwo heteroatoms. In embodiments, the alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclyl, or heteroaryl with which the exocyclic doublebond is substituted, as well as the exocyclic spiro ring optionallyformed by R¹⁷ and R¹⁸, are optionally substituted with groups such assubstituents that do no interfere unacceptably with the catalytic actionof the respective ligand when used in combination with transition metalcompounds. In embodiments, these optional substituents are selected fromthose groups described for R¹ and R².

In addition to, or alternatively, each of R¹⁷ and R¹⁸ may beindependently selected from moieties that do not interfere unacceptablywith the catalytic action of the respective ligand when used incombination with transition metal compounds. Each of R¹⁷ and R¹⁸ may beindependently selected from hydrogen, halo, fluoro, alkyl, alkenyl,alkynyl, haloalkyl, fluoroalkyl, alkyloxy, alkylthio, N-alkylamino,N,N-dialkylamino, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocycloalkyl, substituted or unsubstitutedM₅-M₆heteroaryl, substituted or unsubstituted phenyl; substituted orunsubstituted arylalkyl; hydroxyalkyl; alkoxyalkyl; aminoalkyl;N-alkylaminoalkyl; N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl;L¹-C(O)—OR^(1′), L¹-P(O)—(OR^(1′))₂, or L¹-S(O)₂—OR^(1′) where R^(1′) ishydrogen, alkyl or hydroxyalkyl and L¹ is a bond or alkylene;L²-O—C(O)—R^(2′) where R^(2′) is alkyl or hydroxyalkyl and L² is a bondor alkylene; L³-C(O)—NR^(3′)R^(4′) where R^(3′) and R^(4′) are hydrogen,alkyl, or hydroxyalkyl and wherein L³ is a bond or alkylene;L⁴-NR^(5′)—C(O)—R^(6′) wherein R^(5′) is hydrogen or alkyl, R^(6′) isalkyl or hydroxyalkyl, and L⁴ is a bond or alkylene.

The phosphacycles may include polycyclic rings with bridging atoms.

Examples of phosphacycles having a structure corresponding to formula(Id) are as follows:

or a salt thereof, wherein R″ is selected from the group consisting ofoxygen, NR²⁰, and C(R²⁰)₂;

R²⁰ is independently, at each occurrence, hydrogen, alkyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl,aryl of arylalkyl and heteroaryl of heteroarylalkyl are optionallysubstituted with alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkylor haloalkoxy; and

n is 0, 1, or 2.

The phosphacycles may have chiral centers such as, for example,phosphacycles 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-37,1-38, 1-39, 1-41, 1-42, 1-43, 1-44, and 1-68.

In embodiments, phosphacycles X are based on rings other than a6-membered ring. Such phosphacycles have structures corresponding to thestructure of formula (Ie):

Phosphacycle X of formula (Ie) may be a 4-membered, 5-membered,7-membered, or 8-membered ring, optionally containing bridging to form apolycyclic ring.

Q¹ may be a bond, —O—, —S—, —N(R²¹)—, ═C(R²²)—, or —C(R²³)(R²⁴)—; Q² maybe a bond, —O—, —S—, —N(R²⁵)—, ═C(R²⁶)—, or —C(R²⁷)(R²⁸)—; Q³ may be abond, —O—, —S—, —N(R²⁹)—, ═C(R³⁰)—, or —C(R³²)(R³⁰)—; Q⁴ may be a bond,—O—, —S—, —N(R³³)—, ═C(R³⁴)—, or —C(R³⁵)(R³⁶)—; and Q⁵ may be a bond,—O—, —S—, —N(R³⁷)—, ═C(R³⁸)—, or —C(R³⁹)(R⁴⁰)—; wherein R¹⁰, R¹¹, R¹²,R¹³, and R²¹ through R⁴⁰ are ring substituents. In embodiments, at leastone of Q₁, Q₂, Q₃, Q₄, and Q₅ is not a bond, so that the phosphacyclehas at least four ring members.

One or more of the ring substituents R²¹ through R⁴⁰ may form a ringwith another ring substituent. In addition, or alternatively, each ofthe ring substituents R²¹ through R⁴⁰ are independently selected fromhydrogen halo, fluoro, alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl,alkyloxy, N-alkylamino, N,N-dialkylamino, N,N,N-trialkylammoniumalkyl;substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted M₅-M₆heteroaryl,substituted or unsubstituted phenyl; hydroxyalkyl; alkoxyalkyl;aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl;N,N,N-trialkylammoniumalkyl; L¹-C(O)—OR^(1′), L¹-P(O)—(OR^(1′))₂, orL¹-S(O)₂—OR^(1′) where R^(1′) is hydrogen, alkyl or hydroxyalkyl and L¹is a bond or alkylene; L²-O—C(O)—R^(2′) where R^(2′) is alkyl orhydroxyalkyl and L² is a bond or alkylene; L³-C(O)—NR^(3′)R^(4′) whereR^(3′) and R^(4′) are each independently hydrogen, alkyl orhydroxyalkyl, and L³ is a bond or alkylene; L⁴-NR^(5′)—C(O)—R^(6′)wherein R^(5′) is hydrogen or alkyl, R^(6′) is alkyl or hydroxyalkyl,and L⁴ is a bond or alkylene; and alkylthio.

In addition, or alternatively, two ring substituents on the same ringatom Q₁, Q₂, Q₃, Q₄, or Q₅ together may form a carbonyl; an exocyclicdouble bond optionally substituted with groups such as alkyl, alkenyl,aryl, cycloalkyl, heterocyclyl, or heteroaryl; or a 3- to 7-memberedSpiro ring containing zero, one, or two hetero ring atoms. Inembodiments, the optional substituents on the exocyclic double bond orspiro ring are selected from the substituents described above for groupsR¹ and R².

In embodiments where a phosphacycle of formula (Ie) is substituted asgroup X on the Ar¹-Ar² group of formula (I), each of R¹ and R² areindependently selected from the group consisting of hydrogen, alkyl,aminoalkyl, and alkoxy; and each of R¹⁰, R¹¹, R¹², and R¹³ areindependently selected from the group consisting of alkyl, aryl, andheteroaryl, and/or R¹⁰ or R¹¹ together with R¹² or R¹³ form a ring.

Non-limiting examples of phosphacycles of formula (Ie) are as follows:

In embodiments, phosphacycles of formula (Ia), (Id), and (Ie), aresubstituted as group X on the Ar¹-Ar² group of formula (I), wherein thegroups R¹ and R² are hydrogen or a non-hydrogen substituent.

In embodiments, X is an acyclic phosphine. In embodiments, X is adialkyl or diaryl phosphine. In embodiments, X is —P(t-butyl)₂.

Phosphine ligands may include, for example,7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane;8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-ol;8-(2′,6′-diisopropoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;1,3,5,7-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane;di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine;di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine;di-tert-butyl(2′-isopropoxy-1,1′-binaphthyl-2-yl)phosphine;2,2,5,5-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phospholane;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphinane;2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphepane;2,2,8,8-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphocane;1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane;8-(2′,6′-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;6-methoxy-N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine;8-(2′-methoxy-1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;7,7,9,9-tetramethyl-8-(2-(naphthalen-1-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane;7,7,9,9-tetramethyl-8-(2-(naphthalen-2-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one;3,3,8,8,10,10-hexamethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane;1-(2′-(dimethylamino)-6′-methoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(2′,6′-bis(dimethylamino)biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(2′,6′-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(2′,6′-diisopropoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(2′-(dimethylamino)biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(1,1′-binaphthyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(2′-methoxy-1,1′-binaphthyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(3,6-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(3,6-dimethoxy-2′,4′,6′-trimethylbiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphinan-4-one;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-4,5-dimethoxybiphenyl-2-yl)phosphinan-4-one;1-(3′,5′-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;1-(4′-tert-butylbiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;N²,N²,N⁶,N⁶-tetramethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2,6-diamine;N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine;8-(biphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;8-(3,6-dimethoxy-2′,4′,6′-trimethylbiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane;di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine;7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane;or any other suitable phosphine. In embodiments, the phosphine ligand is7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane.In embodiments, the phosphine ligand is8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane.In embodiments, the phosphine ligand is2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-ol.In embodiments, the phosphine ligand is8-(2′,6′-diisopropoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is1,3,5,7-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane.In embodiments, the phosphine ligand isdi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine.In embodiments, the phosphine ligand isdi-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine. Inembodiments, the phosphine ligand isdi-tert-butyl(2′-isopropoxy-1,1′-binaphthyl-2-yl)phosphine. Inembodiments, the phosphine ligand is2,2,5,5-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phospholane.In embodiments, the phosphine ligand is2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphinane.In embodiments, the phosphine ligand is2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphepane.In embodiments, the phosphine ligand is2,2,8,8-tetramethyl-1-(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphocane.In embodiments, the phosphine ligand is1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane.In embodiments, the phosphine ligand is8-(2′,6′-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is6-methoxy-N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine.In embodiments, the phosphine ligand is8-(2′-methoxy-1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is7,7,9,9-tetramethyl-8-(2-(naphthalen-1-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is7,7,9,9-tetramethyl-8-(2-(naphthalen-2-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one.In embodiments, the phosphine ligand is3,3,8,8,10,10-hexamethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane.In embodiments, the phosphine ligand is1-(2′-(dimethylamino)-6′-methoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one.In embodiments, the phosphine ligand is1-(2′,6′-bis(dimethylamino)biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one.In embodiments, the phosphine ligand is1-(2′,6′-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. Inembodiments, the phosphine ligand is1-(2′,6′-diisopropoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one.In embodiments, the phosphine ligand is1-(2′-(dimethylamino)biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one.In embodiments, the phosphine ligand is1-(biphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. In embodiments,the phosphine ligand is1-(1,1′-binaphthyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. Inembodiments, the phosphine ligand is1-(2′-methoxy-1,1′-binaphthyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one.In embodiments, the phosphine ligand is1-(3,6-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. Inembodiments, the phosphine ligand is1-(3,6-dimethoxy-2′,4′,6′-trimethylbiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one;2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphinan-4-one.In embodiments, the phosphine ligand is2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropyl-4,5-dimethoxybiphenyl-2-yl)phosphinan-4-one;1-(3′,5′-dimethoxybiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. Inembodiments, the phosphine ligand is1-(4′-tert-butylbiphenyl-2-yl)-2,2,6,6-tetramethylphosphinan-4-one. Inembodiments, the phosphine ligand isN²,N²,N⁶,N⁶-tetramethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2,6-diamine.In embodiments, the phosphine ligand isN,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine.In embodiments, the phosphine ligand is8-(biphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is8-(3,6-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand is8-(3,6-dimethoxy-2′,4′,6′-trimethylbiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane.In embodiments, the phosphine ligand isdi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine.In embodiments, the phosphine ligand is7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane.

Compound (5) may be sulfonamidated in the presence of a catalyst and/ora catalyst precursor. In embodiments, the catalyst and/or a catalystprecursor is a transition metal compound. In embodiments, the transitionmetal catalyst or the transition metal catalyst precursor is a palladiumcatalyst or a palladium catalyst precursor, respectively. Palladiumcatalysts or palladium catalyst precursors may include, for example,tetrakis(triphenylphosphine)palladium(0),dichlorobis(tri-o-tolylphosphine)palladium(II), palladium(II) acetate,[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II),bis(dibenzylideneacetone) palladium(0), tris(dibenzylideneacetone)dipalladium(0), tris(dibenzylideneacetone) dipalladium(0) chloroformadduct, dichlorobis(tricyclohexylphosphine) palladium(II),dichlorobis(triphenylphosphine) palladium(II),chloro(η3-allyl)palladium(II) dimer-triphenylphosphine, palladium(II)chloride, palladium(II) bromide, bis(acetonitrile)dichloropalladium(II)and any other suitable palladium catalyst or palladium catalystprecursor. In embodiments, the palladium catalyst precursor or palladiumcatalyst precursor is tetrakis(triphenylphosphine) palladium(0). Inembodiments, the palladium catalyst or palladium catalyst precursor isdichlorobis(tri-o-tolylphosphine) palladium(II). In embodiments, thepalladium catalyst or palladium catalyst precursor is palladium(II)acetate. In embodiments, the palladium catalyst or palladium catalystprecursor is [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In embodiments, the palladium catalyst or palladiumcatalyst precursor is tris(dibenzylideneacetone) dipalladium(0). Inembodiments, the palladium catalyst or palladium catalyst precursor isbis(dibenzylideneacetone) palladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor is palladium(II) bromide. Inembodiments, the palladium catalyst or palladium catalyst precursor ispalladium(II) chloride. In embodiments, the palladium catalyst orpalladium catalyst precursor is bis(acetonitrile)dichloropalladium(II).In embodiments, the palladium catalyst or palladium catalyst precursoris dichlorobis(tricyclohexylphosphine) palladium(II). In embodiment, thepalladium catalyst or palladium catalyst precursor isdichlorobis(triphenylphosphine) palladium(II). In embodiment, thepalladium catalyst or palladium catalyst precursor ischloro(η3-allyl)palladium(II) dimer-triphenylphosphine.

In embodiments, compound (5) is sulfonamidated in the presence ofsolvent. Solvents may include, for example, tetrahydrofuran,N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone,dimethyl sulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile,cyclopentyl methyl ether, toluene, benzene, tert-amyl alcohol, andtert-butyl alcohol, 2-methyltetrahydrofuran, ethyl acetate, isopropylacetate, anisole, trifluorotoluene and any other suitable solvent andcombinations thereof. In embodiments, the solvent is tetrahydrofuran. Inembodiments, the solvent is N,N-dimethylformamide. In embodiments, thesolvent is N,N-dimethylacetamide. In embodiments, the solvent isN-methylpyrrolidone. In embodiments, the solvent is dimethyl sulfoxide.In embodiments, the solvent is 1,2-dimethoxyethane. In embodiments, thesolvent is 1,4-dioxane. In embodiments, the solvent is acetonitrile. Inembodiments, the solvent is cyclopentyl methyl ether. In embodiments,the solvent is toluene. In embodiments, the solvent is benzene. Inembodiments, the solvent is tert-amyl alcohol. In embodiments, thesolvent is tert-butyl alcohol. In embodiments, the solvent is2-methyltetrahydrofuran. In embodiments, the solvent is ethyl acetate.In embodiments, the solvent is isopropyl acetate. In embodiments, thesolvent is anisole. In embodiments, the solvent is trifluorotoluene. Inembodiments, the solvent is a mixture of 2-methyltetrahydrofuran andethyl acetate. In embodiments, the solvent is a mixture of tert-amylalcohol and dimethyl sulfoxide. In embodiments, the solvent is a 7:1mixture of tert-amyl alcohol and dimethyl sulfoxide. In embodiments, thesolvent is a 1:2 mixture of 2-methyltetrahydrofuran and ethyl acetate.In embodiments, the solvent is a 1:3 mixture of 2-methyltetrahydrofuranand ethyl acetate.

Compound (5) may be sulfonamidated in the presence of base. Bases mayinclude, for example, potassium phosphate tribasic, cesium carbonate,potassium carbonate, sodium carbonate, sodium tert-butoxide, potassiumtert-butoxide, sodium phenoxide, lithium bis(trimethylsilyl)amide,lithium diisopropylamide and any other suitable base and combinationsthereof. In embodiments, the base is potassium phosphate tribasic. Inembodiments, the base is potassium phosphate tribasic with a particlesize (D90) less than or equal to 120 μm. In embodiments, the base ispotassium phosphate tribasic hydrated with less than one molarequivalent of water. In embodiments, the base is potassium phosphatetribasic hydrated with less than 0.5 molar equivalents of water. Inembodiments, the base is potassium phosphate tribasic with a particlesize (D90) less than or equal to 120 μm and hydrated with less than onemolar equivalent of water. In embodiments, the base is potassiumphosphate tribasic with a particle size (D90) less than or equal to 120μm and hydrated with less than 0.5 molar equivalent of water. Inembodiments, the base is cesium carbonate. In embodiments, the base ispotassium carbonate. In embodiments, the base is sodium carbonate. Inembodiments, the base is sodium tert-butoxide. In embodiments, the baseis potassium tert-butoxide. In embodiments, the base is sodiumphenoxide. In embodiments, the base is lithium bis(trimethylsilyl)amide.In embodiments, the base is lithium diisopropylamide.

Compound (5) may be sulfonamidated at a temperature of from about 20° C.to about 130° C. or from about 60° C. to about 100° C. In instanceswhere the reaction is conducted above the boiling point of the reactionsolvent, the reaction is conducted in a sealed vessel suitable tocontain the pressure of the reaction. In embodiments, compound (5) issulfonamidated at a temperature of about 60° C., then about 85° C., andfinally about 95° C. In embodiments, compound (5) is sulfonamidated at atemperature of about 80° C. and then about 50° C. In embodiments,compound (5) is sulfonamidated at a temperature of about 80° C. and thenabout 90° C.

Compound (5) may be sulfonamidated in an inert atmosphere. Inembodiments, the inert atmosphere is provided by nitrogen. Inembodiments, the inert atmosphere is provided by argon.

In an embodiment, compound (5) is reacted with methanesulfonamide underan argon atmosphere in t-amyl alcohol in the presence of potassiumphosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) anddi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide underan argon atmosphere in t-amyl alcohol in the presence of potassiumphosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane togive compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-olto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and8-(2′,6′-diisopropoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and1,3,5,7-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and8-(2′,6′-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and6-methoxy-N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and8-(2′-methoxy-1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide in1-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and7,7,9,9-tetramethyl-8-(2-(naphthalen-1-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) and7,7,9,9-tetramethyl-8-(2-(naphthalen-2-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide intetrahydrofuran in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) anddi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide in2-methyltetrahydrofuran in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) anddi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide inethyl acetate in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) anddi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide int-amyl alcohol in the presence of potassium phosphate tribasic,tris(dibenzylideneacetone)dipalladium(0) anddi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide in amixture of 2-methyltetrahydrofuran and ethyl acetate in the presence ofpotassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0)anddi-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphineto give compound (A).

In an embodiment, compound (5) is reacted with methanesulfonamide in amixture of 2-methyltetrahydrofuran and ethyl acetate in the presence ofpotassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0)and7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decaneto give compound (A).

Compounds of formula (A) may be converted to a corresponding salt. Asalt of compound (A) may be advantageous due to one or more of theproperties of the salt, such as, for example, enhanced pharmaceuticalstability in differing temperatures and humidities, or a desirablesolubility in water or other solvents. Where a salt is intended to beadministered to a patient (as opposed to, for example, being in use inan in vitro context), the salt is considered to be pharmaceuticallyacceptable and/or physiologically compatible. Accordingly, the term“pharmaceutically acceptable” is used adjectivally in this disclosure tomean that the modified noun is appropriate for use as a pharmaceuticalproduct or as a part of a pharmaceutical product. Pharmaceuticallyacceptable salts include salts commonly used to form alkali metal saltsand to form addition salts of free acids or free bases. In general,these salts typically may be prepared by conventional means by reacting,for example, the appropriate acid or base with a compound of thedisclosure. Pharmaceutically acceptable base addition salts of thecompounds of formula (A) include, for example, metallic salts andorganic salts. Metallic salts may include alkali metal (group Ia) salts,alkaline earth metal (group IIa) salts, and other physiologicallyacceptable metal salts. Such salts may be made from aluminum, calcium,lithium, magnesium, potassium, sodium, and zinc.

The salt of compound (A) may be the potassium salt, the sodium salt orany other suitable salt. In embodiments, the salt of compound (A) is thepotassium salt. In embodiments, the salt of compound (A) is the sodiumsalt. In an embodiment, compounds of formula (A) may be converted to thecorresponding salt, compound (A-s), by treatment with a base, solvent orbase in a solvent. For convenient illustration, the salt is shown ashaving formed at the uracil group as is shown with formula (A-s). Thesulfonamide moiety is also a functional group capable of salt formationas illustrated with formula (A-s′). The actual site of salt formationmay be at either functional group.

Bases may include, for example, potassium hydroxide, sodium hydroxideand any other suitable base. In embodiments, the base is potassiumhydroxide. In embodiments, the base is sodium hydroxide. Solvents mayinclude, for example, dimethyl sulfoxide, 2-propanol, water, and anyother suitable solvent or mixtures thereof. In an embodiment, compound(A) is reacted with sodium hydroxide in a mixture of dimethyl sulfoxide,2-propanol and water to give compound (A-s) as the sodium salt. In anembodiment the conversion to the corresponding salt is conducted at atemperature of about 68° C.

Organic salts of compound (A) may be made from amines, such astromethamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine. Basic nitrogen-containing groups canbe quaternized with agents such as lower alkyl (C₁-C₆) halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl, andstearyl chlorides, bromides, and iodides), arylalkyl halides (e.g.,benzyl and phenethyl bromides), and others.

In addition to preparing disclosed compounds, the disclosure is alsodirected to processes for preparing particular salts and polymorphs ofcertain disclosed compounds, including intermediates of the disclosedprocesses, as well as compositions comprising such compounds, salts, andpolymorphs. For example, this disclosure is directed, in part, topreparing crystalline forms ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(compound (A-1)) and the corresponding sodium and potassium salts,namely the solvate, hydrate, and solvent-free crystalline formsdescribed in International Patent Publication Nos. WO 2009/039134 andWO2009/039127 which are incorporated herein by reference.

B. Process for Preparing6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Compound (5-I)

Compound (5-I) may be prepared by reacting1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4)) with a sulfonyl fluoride, sulfonyl chloride, or sulfonicacid anhydride, wherein X¹ is bromo, chloro, fluoro,N-phenyl-trifluoromethylsulfonamidyl, or aryloxy such as 4-nitrophenoxy,and R^(1a) is independently, at each occurrence, aryl, such as p-tolylor phenyl; alkyl such as methyl or ethyl; fluoroalkyl such astrifluoromethyl, perfluorobutyl, or isomers of perfluorobutyl and otherhigher and lower homologs such as, but not limited to, perfluoropentyl,perfluorohexyl, and perfluorooctyl; fluoroalkoxyfluoroalkyl such asperfluoroethoxyethyl; —N(alkyl)₂; fluoro; —O(alkyl) and —O(aryl); orimidazolyl:

Compound (4) may be sulfonylated in the presence of a base. Bases mayinclude, for example, sodium hydride, sodium hydroxide, sodiummethoxide, sodium ethoxide, sodium tert-butoxide, potassium hydride,potassium hydroxide, potassium methoxide, potassium ethoxide, potassiumtert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate,sodium bicarbonate, triethylamine, diisopropylethylamine,4-methylmorpholine, pyridine, 2,6-dimethylpyridine, or any othersuitable base. In embodiments, the base is sodium hydride. Inembodiments, the base is sodium hydroxide. In embodiments, the base issodium methoxide. In embodiments, the base is sodium ethoxide. Inembodiments, the base is sodium tert-butoxide. In embodiments, the baseis potassium hydride. In embodiments, the base is potassium hydroxide.In embodiments, the base is potassium methoxide. In embodiments, thebase is potassium ethoxide. In embodiments, the base is potassiumtert-butoxide. In embodiments, the base is potassium carbonate. Inembodiments, the base is cesium carbonate. In embodiments, the base issodium carbonate. In embodiments, the base is sodium bicarbonate. Inembodiments, the base is triethylamine. In embodiments, the base isdiisopropylethylamine. In embodiments, the base is 4-methylmorpholine.In embodiments, the base is pyridine. In embodiments, the base is2,6-dimethylpyridine.

Compound (4) may be sulfonylated in the presence of solvent. Solventsmay include, for example, tetrahydrofuran, 2-methyltetrahydrofuran,dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile,dichloromethane, chloroform, diethyl ether, or any other suitablesolvent or mixtures thereof. In embodiments, the solvent istetrahydrofuran. In embodiments, the solvent is 2-methyltetrahydrofuran.In embodiments, the solvent is dimethyl sulfoxide. In embodiments, thesolvent is N,N-dimethylformamide. In embodiments, the solvent isN,N-dimethylacetamide. In embodiments, the solvent isN-methylpyrrolidone. In embodiments, the solvent is 1,2-dimethoxyethane.In embodiments, the solvent is 1,4-dioxane. In embodiments, the solventis acetonitrile. In embodiments, the solvent is dichloromethane. Inembodiments, the solvent is chloroform. In embodiments, the solvent isdiethyl ether. In embodiments, the solvent is a mixture ofN,N-dimethylformamide and acetonitrile. In embodiments, the solvent is a2:3 mixture of N,N-dimethylformamide and acetonitrile.

Compound (4) may be sulfonylated at a temperature of from about −15° C.to about 50° C. or from about −5° C. to about 30° C. In an embodiment,compound (4) is sulfonylated at ambient temperature.

Compound (4) may be sulfonylated in ambient atmosphere or inertatmosphere. In embodiments, the atmosphere is ambient. In embodiments,the inert atmosphere is provided by nitrogen. In embodiments, the inertatmosphere is provided by argon.

In an embodiment, compound (4) is reacted with perfluorobutanesulfonylfluoride under an inert nitrogen atmosphere in N,N-dimethylformamide atambient temperature in the presence of potassium carbonate to providecompound (5a).

In an embodiment, compound (4a) is reacted with perfluorobutanesulfonylfluoride under an inert nitrogen atmosphere in a mixture ofN,N-dimethylformamide and acetonitrile at ambient temperature in thepresence of potassium carbonate to provide compound (5a).

In an embodiment, compound (4a) is reacted with1,1,2,2,3,3,3-heptafluoropropane-1-sulfonyl fluoride under an inertnitrogen atmosphere in N,N-dimethylformamide at ambient temperature inthe presence of potassium carbonate to provide6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,-heptafluoropropane-1-sulfonate, compound (5b).

In an embodiment, compound (4a) is reacted with1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride under an inertnitrogen atmosphere in N,N-dimethylformamide at ambient temperature inthe presence of potassium carbonate to provide6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate, compound (5c).

In an embodiment, compound (4a) is reacted with1,1,2,2,2-pentafluoroethanesulfonyl fluoride under an inert nitrogenatmosphere in N,N-dimethylformamide at ambient temperature in thepresence of potassium carbonate to provide compound6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,2-pentafluoroethanesulfonate, compound (5d).

In an embodiment, compound (4a) is reacted with trifluoromethanesulfonylfluoride under an inert nitrogen atmosphere in N,N-dimethylformamide atambient temperature in the presence of potassium carbonate to provide6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yltrifluoromethanesulfonate, compound (5e).

In an embodiment, compound (4a) is reacted withperfluoro(2-ethoxyethane)sulfonyl fluoride under an inert nitrogenatmosphere in N,N-dimethylformamide at ambient temperature in thepresence of potassium carbonate to provide6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate, compound (5f).

In an embodiment, compound (4a) is reacted with sulfuryl fluoride underan inert nitrogen atmosphere in N,N-dimethylformamide at ambienttemperature in the presence of potassium carbonate to provide6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylsulfofluoridate, compound (5g).

C. Process for Preparing Compounds of Formula (4) such as1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (4))

This disclosure is directed, in part, to compound (4) such as1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4a)) or a salt thereof. Compound (4) may be prepared byreacting compound (1) with compound (3) under cross-coupling reactionconditions in the presence of a transition metal catalyst or atransition metal catalyst precursor and ligand, and base.

R⁴ and R⁵ are as described above. LG² of compound (1) may be chloro,bromo, iodo, or —OSO₂R^(1b), wherein R^(1b) is selected from aryl, suchas p-tolyl or phenyl; alkyl such as methyl or ethyl; fluoroalkyl such astrifluoromethyl, perfluorobutyl, or isomers of perfluorobutyl and otherhigher and lower homologs such as, but not limited to, perfluoropentyl,perfluorohexyl, and perfluorooctyl; perfluroalkoxyfluoroalkyl such asperfluoroethoxyethyl; fluoro; —N(alkyl)₂; —O(alkyl) and —O(aryl); orimidazolyl. In embodiments, LG² is chloro. In embodiments, LG² is bromo.In embodiments, LG² is iodo. In embodiments, LG² is —OSO₂-p-tolyl. Inembodiments, LG² is —OSO₂-phenyl. In embodiments, LG² is —OSO₂CH₃. Inembodiments, LG² is —OSO₂CF₃. In embodiments, LG² is —OSO₂C₄F₉. Inembodiments, LG² is —OSO₂N(CH₃)₂. Compound (1) may include, for example,1-(3-tert-butyl-5-chloro-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (1a)),1-(3-bromo-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (1b)), or1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (1c)). The preparation of compound (1) is described in Example1 below as well as in International Patent Publication No. WO2009/039127 which is incorporated herein by reference.

Y¹ of compound (3) is selected from the group consisting of anorganoborane; boronic acid; borate ester; borate salt; zinc halide;zincate; organomagnesium; magnesium halide; magnesium alkoxide; lithium;—Si(R^(1c))₄ and —Sn(R^(1d))₄, wherein R^(1c) and R^(1d) are selectedfrom the group consisting of alkyl, phenyl, hydroxy, halide, hydride,and alkoxy. In embodiments, Y¹ is a boronic acid. In embodiments, Y¹ isa borate ester. In embodiments, Y¹ is a borate salt. Compound (3) mayinclude, for example, 6-hydroxynaphthalen-2-ylboronic acid (compound(3a)), potassium trifluoro(6-hydroxynaphthalen-2-yl)borate (compound(3b)), and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (compound(3c)), each of which are commercially available.

The cross-coupling reaction may be conducted in the presence of catalystor a catalyst precursor. The catalyst or catalyst precursor maycomprise, for example, copper, nickel, palladium, or other suitablemetal or mixtures thereof. In embodiments, the catalyst is a transitionmetal catalyst and/or a transition metal catalyst precursor. Inembodiments, the transition metal catalyst or the transition metalcatalyst precursor is a palladium catalyst or palladium catalystprecursor. Palladium catalysts or palladium catalyst precursors mayinclude, for example, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),tris(dibenzylidineacetone)dipalladium(0),tris(dibenzylidineacetone)dipalladium(0) chloroform adduct,bis(dibenzylidineacetone)palladium(0), palladium(II) diacetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, or any other suitable palladium catalyst orpalladium catalyst precursor. In embodiments, the palladium catalyst orpalladium catalyst precursor istetrakis(triphenylphosphine)palladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor isdichlorobis(triphenylphosphine)palladium(II). In embodiments, thepalladium catalyst or palladium catalyst precursor istris(dibenzylidineacetone)dipalladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor isbis(dibenzylidineacetone)palladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor is palladium(II) diacetate. Inembodiments, the palladium catalyst or palladium catalyst precursor isdichlorobis(triphenylphosphine)palladium(II). In embodiments, thepalladium catalyst or palladium catalyst precursor is[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane.

The cross-coupling reaction may be conducted in the presence of aligand. In embodiments the ligand is a phosphine. Ligands may include,for example, tri-t-butylphosphine, tricyclohexylphosphine,tris(2-furyl)phosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane,biphenyl-2-yldicyclohexylphosphine,dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine,dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine,[4-(dimethylamino)phenyl]bis(tert-butyl)phosphine or any other suitableligand or salts thereof. In embodiments, the ligand istri-t-butylphosphine. In embodiments, the ligand istricyclohexylphosphine. In embodiments, the ligand is,tris(2-furyl)phosphine. In embodiments, the ligand is2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. In embodiments, the ligandis1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane.In embodiments, the ligand is biphenyl-2-yldicyclohexylphosphine. Inembodiments, the ligand isdicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine. In embodiments, theligand is dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine. Inembodiments, the ligand is[4-(dimethylamino)phenyl]bis(tert-butyl)phosphine.

Compound (1) may be reacted with compound (3) in the presence of a base.Bases may include, for example, potassium phosphate tribasic, cesiumcarbonate, potassium carbonate, sodium carbonate, potassiumtert-butoxide, cesium fluoride, potassium hydroxide or any othersuitable base. In embodiments, the base is potassium phosphate tribasic.In embodiments, the base is cesium carbonate. In embodiments, the baseis potassium carbonate. In embodiments, the base is sodium carbonate. Inembodiments, the base is potassium tert-butoxide. In embodiments, thebase is cesium fluoride. In embodiments, the base is potassiumhydroxide.

Compound (1) may be reacted with compound (3) in the presence ofsolvent. Solvents may include, for example, tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, 1,2-dimethoxyethane,1,4-dioxane, ethanol, toluene, water, or any other suitable solvent ormixtures thereof. In embodiments, the solvent is tetrahydrofuran. Inembodiments, the solvent is 2-methyltetrahydrofuran. In embodiments, thesolvent is N,N-dimethylformamide. In embodiments, the solvent is1,2-dimethoxyethane. In embodiments, the solvent is 1,4-dioxane. Inembodiments, the solvent is ethanol. In embodiments, the solvent istoluene. In embodiments, the solvent is water. In embodiments, thesolvent is a tetrahydrofuran and water mixture. In embodiments, thesolvent is water. In embodiments, the solvent is a 3:1 mixture oftetrahydrofuran and water.

Compound (1) may be reacted with compound (3) at a temperature of fromabout 20° C. to about 130° C., or from about 40° C. to about 80° C. Ininstances where the reaction is conducted above the boiling point of thereaction solvent, the reaction is conducted in a sealed vessel suitableto contain the pressure of the reaction. In an embodiment the reactionis conducted at ambient or elevated temperatures. In an embodiment thereaction is conducted at about 65° C. The heating may be provided eitherthrough conventional or microwave heating.

Compound (1) may be reacted with compound (3) in an inert atmosphere. Inembodiments, the inert atmosphere is provided by nitrogen. Inembodiments, the inert atmosphere is provided by argon.

In an embodiment,1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (1c) is reacted with 6-hydroxynaphthalen-2-ylboronic acid(compound (3a) in tetrahydrofuran in the presence of potassium phosphatetribasic,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane,and tris(dibenzylideneacetone)dipalladium(0) to provide1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4a)).

In an embodiment,1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (1c) is reacted with 6-hydroxynaphthalen-2-ylboronic acid(compound (3a) in a mixture of tetrahydrofuran and water in the presenceof potassium phosphate tribasic,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane,and tris(dibenzylideneacetone)dipalladium(0) to provide1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4a)).

Compounds of formula (4) such as1-(3-tert-Butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4a)) may also be prepared by reacting compound (1-Y²) withcompound (3-LG³) under cross-coupling reaction conditions in thepresence of a transition metal catalyst and/or a transition metalcatalyst precursor, base, and ligand.

LG³ of compound (3-LG³) may be chloro, bromo, iodo, or —OSO₂R^(1b),wherein R^(1b) is selected from aryl, such as p-tolyl or phenyl; alkylsuch as methyl or ethyl; fluoroalkyl such as trifluoromethyl,perfluorobutyl, or isomers of perfluorobutyl and other higher and lowerhomologs such as, but not limited to, perfluoropentyl, perfluorohexyl,and perfluorooctyl; perfluoroethoxyethyl; fluoro; —N(alkyl)₂; —O(alkyl)and —O(aryl); or imidazolyl. In embodiments, LG³ is chloro. Inembodiments, LG³ is bromo. In a further embodiment, LG³ is iodo. Inembodiments, LG³ is —OSO₂-p-tolyl. In embodiments, LG³ is —OSO₂-phenyl.In embodiments, LG³ is —OSO₂CH₃. In embodiments, LG³ is —OSO₂CF₃. Inembodiments, LG³ is —OSO₂C₄F₉. In embodiments, LG³ is —OSO₂N(CH₃)₂.Compound (3-LG³) may include, for example, 6-chloronaphthalen-2-ol(compound (3-LG³a)), 6-bromonaphthalen-2-ol (compound (3-LG³b)), or6-iodonaphthalen-2-ol (compound (3-LG³c)). Compounds of formula (3-LG³)are either commercially available or can be prepared by methods known toone skilled in the art.

Y² of compound (1-Y²) is selected from the group consisting of anorganoborane; boronic acid; borate ester; borate salt; zinc halide;zincate; organomagnesium; magnesium halide; magnesium alkoxide; lithium;—Si(R^(1c))₄ and —Sn(R^(1d))₄, wherein R^(1c) and R^(1d) are selectedfrom the group consisting of alkyl, phenyl, hydroxy, halide, hydride,and alkoxy. In embodiments, Y² is a boronic acid. In embodiments, Y² isa borate ester. In embodiments, Y³ is a borate salt. Compound (1-Y²) mayinclude, for example,3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylboronicacid (compound (1-Y²a)), potassium(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)trifluoroborate(compound (1-Y²b)), and1-(3-tert-butyl-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione(compound (1-Y²c)). Compounds of formula (1-Y²) may be prepared fromcompounds of formula (1) by methods known to one skilled in the art.

The cross-coupling reaction may be conducted in the presence of catalystor catalyst precursor. The catalyst or catalyst precursor may comprise,for example, copper, nickel, palladium, or other suitable metal ormixtures thereof. In embodiments, the catalyst or catalyst precursor isa transition metal catalyst and/or a transition metal catalystprecursor. In embodiments, the transition metal catalyst or thetransition metal catalyst precursor is a palladium catalyst or palladiumcatalyst precursor. Palladium catalysts or palladium catalyst precursorsmay include, for example, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),tris(dibenzylidineacetone)dipalladium(0),bis(dibenzylidineacetone)palladium(0), palladium(II) diacetate,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, or any other suitable palladium catalyst orpalladium catalyst precursor. In embodiments, the palladium catalyst orpalladium catalyst precursor istetrakis(triphenylphosphine)palladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor isdichlorobis(triphenylphosphine)palladium(II). In embodiments, thepalladium catalyst or palladium catalyst precursor istris(dibenzylidineacetone)dipalladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor isbis(dibenzylidineacetone)palladium(0). In embodiments, the palladiumcatalyst or palladium catalyst precursor is palladium(II) diacetate. Inembodiments, the palladium catalyst or palladium catalyst precursor isdichlorobis(triphenylphosphine)palladium. In embodiments, the palladiumcatalyst or palladium catalyst precursor is[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane.

The cross-coupling reaction may be conducted in the presence of aligand. In embodiments the ligand is a phosphine. Ligands or saltsthereof may include, for example, tri-t-butylphosphine,tricyclohexylphosphine, tris(2-furyl)phosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane,biphenyl-2-yldicyclohexylphosphine,dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine,dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine, or any othersuitable ligand. In embodiments, the ligand is tri-t-butylphosphine. Inembodiments, the ligand is tricyclohexylphosphine. In embodiments, theligand is, tris(2-furyl)phosphine. In embodiments, the ligand is2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. In embodiments, the ligandis1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane.In embodiments, the ligand is biphenyl-2-yldicyclohexylphosphine. Inembodiments, the ligand isdicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine. In embodiments, theligand is dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine.

Compound (1-Y²) may be reacted with compound (3-LG³) in the presence ofa base. Bases may include, for example, potassium phosphate tribasic,cesium carbonate, potassium carbonate, sodium carbonate, potassiumtert-butoxide, cesium fluoride, potassium hydroxide or any othersuitable base. In embodiments, the base is potassium phosphate tribasic.In embodiments, the base is cesium carbonate. In embodiments, the baseis potassium carbonate. In embodiments, the base is sodium carbonate. Inembodiments, the base is potassium tert-butoxide. In embodiments, thebase is cesium fluoride. In embodiments, the base is potassiumhydroxide.

Compound (1-Y²) may be reacted with compound (3-LG³) in the presence ofsolvent. Solvents may include, for example, tetrahydrofuran,2-methyltetrahydrofuran, N,N-dimethylformamide, 1,2-dimethoxyethane,1,4-dioxane, ethanol, toluene, water, or any other suitable solvent ormixtures thereof. In embodiments, the solvent is tetrahydrofuran. Inembodiments, the solvent is 2-methyltetrahydrofuran. In embodiments, thesolvent is N,N-dimethylformamide. In embodiments, the solvent is1,2-dimethoxyethane. In embodiments, the solvent is 1,4-dioxane. Inembodiments, the solvent is ethanol. In embodiments, the solvent istoluene. In embodiments, the solvent is water.

Compound (1-Y²) may be reacted with compound (3-LG³) at a temperature offrom about 20° C. to about 130° C., or from about 40° C. to about 80° C.In instances where the reaction is conducted above the boiling point ofthe reaction solvent, the reaction is conducted in a sealed vesselsuitable to contain the pressure of the reaction. In an embodiment thereaction is conducted at ambient or elevated temperatures. In anembodiment the reaction is conducted at about 65° C. The temperature maybe controlled either through conventional or microwave heating.

Compound (1-Y²) may be reacted with compound (3-LG³) in an inertatmosphere. In embodiments, the inert atmosphere is provided bynitrogen. In embodiments, the inert atmosphere is provided by argon.

In an embodiment,3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylboronicacid (compound (1-Y²a)) is reacted with 6-iodonaphthalen-2-ol (compound(3-LG³c)) in tetrahydrofuran in the presence of potassium phosphatetribasic,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane,and tris(dibenzylideneacetone)dipalladium(0) to provide1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(compound (4a)).

D. Definitions

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁-C₆ alkyl” means a straight or branched chain hydrocarboncontaining 1 to 6 carbon atoms. The term “C₁₋₃ alkyl” means a straightor branched chain hydrocarbon containing 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylamino” or “N-alkylamino” as used herein, means an alkylgroup, as defined herein, appended to the parent molecular moietythrough an amino group, as defined herein. Representative examples ofalkylamino include, but are not limited to, methylamino, ethylamino, andsec-butylamino.

The term “N-alkylaminoalkyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through anaminoalkyl group, as defined herein. Representative examples ofN-alkylaminoalkyl include, but are not limited to, methylaminoethyl andmethylamino-2-propyl.

The term “alkylcarbonyl” means an alkyl group appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of alkylcarbonyl include, but are not limitedto, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and1-oxopentyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon 1 to 10 carbon atoms. Representative examplesof alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “N-(alkyl)sulfamoyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfamoyl group, as defined herein. Representative examples ofN-(alkyl)sulfamoyl include, but are not limited to, N-methylsulfamoyland N-ethylsulfamoyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited to,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “amino” as used herein means an —NH₂ group.

The term “aminoalkyl” as used herein means at least one amino group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of aminoalkyl include,but are not limited to, aminomethyl, 2-aminoethyl,2-methyl-2-hydroxyethyl, and 2-aminopropyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the aryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present disclosure can be unsubstituted or substituted.

The term “arylalkyl,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkyl group. Representativeexamples of arylalkyl include, but not limited to, phenylmethyl,phenylethyl and naphthylmethyl.

The term “carbonyl” as used herein, refers to —C(═O).

The term “cyano” as used herein, means a —CN group.

The term “cycloalkoxy” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of cycloalkoxy include, but are notlimited to, cyclohexyloxy and cyclopropoxy.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicycliccycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkylring, or a bridged monocyclic ring system in which two non-adjacentcarbon atoms of the monocyclic ring are linked by an alkylene bridgecontaining one, two, three, or four carbon atoms. Representativeexamples of bicyclic ring systems include, but are not limited to,bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.Tricyclic cycloalkyls are exemplified by a bicyclic cycloalkyl fused toa monocyclic cycloalkyl, or a bicyclic cycloalkyl in which twonon-adjacent carbon atoms of the ring systems are linked by an alkylenebridge of 1, 2, 3, or 4 carbon atoms. Representative examples oftricyclic-ring systems include, but are not limited to,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). Themonocyclic, bicyclic, and tricyclic cycloalkyls can be unsubstituted orsubstituted, and are attached to the parent molecular moiety through anysubstitutable atom contained within the ring system.

The term “dialkylamino” or “N,N-dialkylamino” as used herein, means twoindependently selected alkyl groups, as defined herein, appended to theparent molecular moiety through an amino group, as defined herein.Representative examples of dialkylamino include, but are not limited to,N,N-dimethylamino, N-ethyl-N-methylamino, and N-isopropyl-N-methylamino.

The term “N,N-dialkylaminoalkyl” as used herein, means two independentlyselected alkyl groups, as defined herein, appended to the parentmolecular moiety through an aminoalkyl group, as defined herein.Representative examples of N,N-dialkylaminoalkyl include, but are notlimited to, N,N-dimethylaminoethyl and N,N-methyl(2-propyl)aminoethyl.

The term “trialkylammoniumalkyl” or “N,N,N-trialkylammoniumalkyl” meansaminoalkyl in which there are three alkyl group substituted on thenitrogen of the amino group resulting in a net positive charge. Thethree substituted alkyl groups can be the same of different. Examples ofN,N,N-trialkylammoniumalkyl include trimethylammoniummethyl anddiethylmethylammoniummethyl.

The term “N,N-(dialkyl)sulfamoyl” as used herein, means twoindependently selected alkyl groups, as defined herein, appended to theparent molecular moiety through a sulfamoyl group, as defined herein.Representative examples of N,N-(dialkyl)sulfamoyl include, but are notlimited to, N,N-dimethylsulfamoyl and N-methyl-N-ethyl-sulfamoyl.

The term “fluoroalkoxy” as used herein, means at least one fluorine, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of fluoroalkoxyinclude, but are not limited to, fluoromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “fluoroalkyl” as used herein means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of fluoroalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, perfluorobutyl, perfluoropentyl, perfluorohexyl,perfluorooctyl pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkyl include, butare not limited to, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive-membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen orsulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl includes a monocyclic heteroaryl fused to a phenyl,or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or amonocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle. Representative examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, 6,7-dihydro-1,3-benzothiazolyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl,naphthyridinyl, pyridoimidazolyl, quinazolinyl, quinolinyl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups of the present disclosure can be substituted or unsubstituted andare connected to the parent molecular moiety through any carbon atom orany nitrogen atom contained within the ring systems.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of oxygen, nitrogen,phosphorus and sulfur. The three- or four-membered ring contains zero orone double bond, and one heteroatom selected from the group consistingof oxygen, nitrogen, phosphorus and sulfur. The five-membered ringcontains zero or one double bond and one, two or three heteroatomsselected from the group consisting of oxygen, nitrogen, phosphorus andsulfur. The six-membered ring contains zero, one or two double bonds andone, two, or three heteroatoms selected from the group consisting ofoxygen, nitrogen, phosphorus and sulfur. The seven- and eight-memberedrings contains zero, one, two, or three double bonds and one, two, orthree heteroatoms selected from the group consisting of oxygen,nitrogen, phosphorus and sulfur. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, phosphinane,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclicheterocycle fused to a phenyl group, or a monocyclic heterocycle fusedto a monocyclic cycloalkyl, or a monocyclic heterocycle fused to amonocyclic cycloalkenyl, or a monocyclic heterocycle fused to amonocyclic heterocycle, or a bridged monocyclic heterocycle ring systemin which two non-adjacent atoms of the ring are linked by an alkylenebridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two,three, or four carbon atoms. Representative examples of bicyclicheterocycles include, but are not limited to, benzopyranyl,benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl,octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl,9-phosphabicyclo[3.3.1]nonane, 8-phosphabicyclo[3.2.1]octane, andtetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by abicyclic heterocycle fused to a phenyl group, or a bicyclic heterocyclefused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to amonocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclicheterocycle, or a bicyclic heterocycle in which two non-adjacent atomsof the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4carbon atoms, or an alkenylene bridge of two, three, or four carbonatoms. Examples of tricyclic heterocycles include, but are not limitedto, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane), and2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane. The monocyclic,bicyclic, and tricyclic heterocycles are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the rings, and can be unsubstituted or substituted.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl(thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl,oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl),oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl(including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), orpyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl(including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl(including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl,or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl,1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl alternatively may be 2 or 3 rings fused together, suchas, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as indolyl, isoindolyl (isobenzazolyl,pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl(benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) orisoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl(1,3-benzodiazinyl)), benzopyranyl (including chromanyl orisochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl,1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), andbenzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkoxy” as used herein, means an hydroxy group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples ofhydroxyalkoxy include, but are not limited to, hydroxyethoxy, and2-hydroxypropoxy.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein, means a ═O group.

The term “oxoalkyl” as used herein, means at least one oxo group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of oxoalkyl include,but are not limited to, acetyl, propan-1-one, propan-2-one, andbutan-2-one.

The term “sulfamate” as used herein, means a —OS(O)₂N(Z³)₂, wherein Z³is hydrogen or an optionally substituted alkyl, aryl, haloalkyl, orheteroaryl, as defined herein. Representative examples of sulfamateinclude, but are not limited to sulfamate and dimethylsulfamate.

The term “sulfamoyl” as used herein, means a —S(O)₂NH₂ group.

The term “sulfate” as used herein, means a Z¹OS(O)₂O—, wherein Z¹ is anoptionally substituted alkyl, aryl, haloalkyl, or heteroaryl, as definedherein. Representative examples of sulfonate include, but are notlimited to, methylsulfate, trifluoromethylsulfate, and phenylsulfate.

The term “sulfonamide” as used herein, means a Z¹S(O)₂N(Z²)— group, asdefined herein, wherein Z¹ is an optionally substituted alkyl, aryl,haloalkyl, or heteroaryl as defined herein, and Z² is hydrogen or alkyl.Representative examples of sulfonamide include, but are not limited to,methanesulfonamide, trifluoromethanesulfonamide, and benzenesulfonamide.

The term “sulfonate” as used herein, means a Z¹S(O)₂O— group, as definedherein, wherein Z¹ is an optionally substituted alkyl, aryl, haloalkyl,or heteroaryl, as defined herein. Representative examples of sulfonateinclude, but are not limited to, methanesulfonate,trifluoromethanesulfonate,1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate, 1H-imidazole-1-sulfonateand p-toluenesulfonate.

The term “thio” or “mercapto” means a —SH group.

The term “thioalkyl” as used herein, means at least one thio group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of thioalkyl include,but are not limited to, thiomethyl or mercaptomethyl and, 2-thioethyl or2-mercaptoethyl.

A substituent is “substitutable” if it comprises at least one carbon ornitrogen atom that is bonded to one or more hydrogen atoms. Thus, forexample, hydrogen, halogen, and cyano do not fall within thisdefinition. In addition, a sulfur atom in a heterocyclyl containing suchatom is substitutable with one or two oxo substituents.

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent in which at least one non-hydrogen radical is inthe place of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there is more than one substitution on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

The terms “substituent” and “radical” are used interchangeably herein.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent in which atleast one hydrogen radical is replaced with a halogen radical. Examplesof haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl substituent wherein a fluorine radicalis in the place of each hydrogen radical.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicatedby the prefix “C_(x)-C_(y)-”, wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl substituent containing from 1 to 6carbon atoms. Illustrating further, C₃-C₆-cycloalkyl means a saturatedhydrocarbyl ring containing from 3 to 6 carbon ring atoms.

As used herein, the number of ring atoms in a heterocyclyl moiety can beidentified by the prefix “M_(x)-M_(y),” where x is the minimum and y isthe maximum number of ring atoms in the heterocyclyl moiety.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Ifthe halogen substitution may only occur on the alkyl component, thesubstituent would instead be described as “alkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent, therefore, may be identical to or different from the othersubstituent(s).

When words are used to describe a substituent, the rightmost-describedcomponent of the substituent is the component that has the free valence.

E. Compositions

This disclosure also is directed, in part, to compositions comprisingthe disclosed compounds or salts thereof or polymorphs thereof, andcompositions comprising compounds or salts thereof or polymorphs thereofprepared by the disclosed processes. In embodiments, compounds offormula (A) such asN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1)) and its salts orpolymorphs thereof prepared by the above processes may be included incompositions. These compositions may also comprise one or moreconventional pharmaceutically acceptable carriers, adjuvants, and/orvehicles (together referred to as “excipients”).

Compositions may include solid dosage forms. Solid dosage forms mayinclude, for example, capsules, tablets, pills, powders, granules or anyother suitable solid dosage form. In such solid dosage forms, thecompounds or salts may be combined with one or more excipients. Ifadministered per os, the compounds or salts may be mixed with, forexample, lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,polyvinyl alcohol or any other suitable excipient, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents, such as sodium citrate, or magnesiumor calcium carbonate, bicarbonate or any other suitable buffering agent.Tablets and pills additionally may be prepared with enteric coatings.

The compounds disclosed herein may be administered as a free acid or asa salt. The compounds or their salts may be administered (in single ordivided doses) in a total daily dose of from about 0.001 to about 100mg/kg, from about 0.001 to about 30 mg/kg, or from about 0.01 to about10 mg/kg (i.e., mg of the compound or salt per kg body weight). Compound(A-1) or a salt thereof may be administered (in single or divided doses)at a total daily dose of from about 4 mg/kg to about 30 mg/kg or fromabout 10 mg/kg to about 25 mg/kg. Compound (A-1) or a salt thereof maybe administered in a total daily dose amount of from about 600 mg toabout 1800 mg or from about 800 mg to about 1600 mg. In an embodiment,compound (A-1) or a salt thereof is administered in a dosage unitcomposition of about 400 mg. In an embodiment, compound (A-1) or a saltthereof is administered in a dosage unit composition of about 800 mg. Inan embodiment, compound (A-1) or a salt thereof is administered in adosage unit composition of about 1200 mg.

Dosage unit compositions may contain such amounts or submultiplesthereof to make up the total daily dose. The administration of thecompound or salt may be repeated a plurality of times. Multiple dosesper day may be used to achieve the total daily dose.

Factors affecting the dosage regimen include the type, age, weight, sex,diet, and condition of the patient; the severity of the pathologicalcondition; the severity of the pathological condition; pharmacologicalconsiderations, such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular compound or salt used; whether adrug delivery system is utilized; and the specific drug combination.Thus, the dosage regimen actually employed can vary widely, andtherefore, can derive from the dosage regimen set forth above.

F. Methods of Use

This disclosure also is directed, in part, to methods of using thedisclosed compounds or salts thereof or polymorphs thereof, compounds orsalts thereof or polymorphs thereof prepared by the disclosed processes,compositions comprising the disclosed compounds or salts thereof orpolymorphs thereof, and compositions comprising compounds or saltsthereof or polymorphs thereof prepared by the disclosed processes.

For example, this disclosure is directed, in part, to methods of usingthe disclosed compounds, salts and compositions for inhibitingreplication of an RNA virus. The methods comprise exposing the virus toa disclosed compound, salt or composition. In embodiments, replicationof the RNA virus is inhibited in vitro. In embodiments, replication ofthe RNA virus is inhibited in vivo. In embodiments, the RNA virus whosereplication is being inhibited is a single-stranded, positive sense RNAvirus. In embodiments, the RNA virus whose replication is beinginhibited is a virus from the Flaviviridae family. In embodiments, theRNA virus whose replication is being inhibited is HCV.

This disclosure is directed, in part, to methods of using the disclosedcompounds, salts and compositions for inhibiting HCV RNA polymerase. Themethods comprise exposing the polymerase to a disclosed compound, saltor composition. In some embodiments, HCV RNA polymerase activity isinhibited in vitro. In some embodiments, HCV RNA polymerase activity isinhibited in vivo.

The term “inhibiting” means reducing the level of RNA virusreplication/HCV polymerase activity either in vitro or in vivo. Forexample, if a composition of the disclosure reduces the level of RNAvirus replication by at least about 10% compared to the level of RNAvirus replication before the virus was exposed to the composition, thenthe composition inhibits RNA virus replication. In some embodiments, thecompound, salt or composition can inhibit RNA virus replication by atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, or at least about 95%.

This disclosure is directed, in part, to methods of using the disclosedcompounds, salts and compositions for treating a disease that can betreated by inhibiting HCV RNA polymerase. Thus, this disclosure also isdirected, in part, to a method for treating hepatitis C in an animal inneed of such treatment. These methods comprise administering to theanimal one or more of the disclosed compounds, salts and compositions.In some embodiments, a therapeutically effective amount of the compound(or salt thereof) is administered to the animal. “Treating” meansameliorating, suppressing, eradicating, preventing, reducing the riskof, and/or delaying the onset of the disease being treated. Applicantsspecifically intend that the term “treating” encompass administration ofthe compositions of the disclosure to an HCV-negative patient that is acandidate for an organ transplant. The methods of treatment areparticularly suitable for use with humans, but may be used with otheranimals, particularly mammals. A “therapeutically-effective amount” or“effective amount” is an amount that will achieve the goal of treatingthe targeted condition.

In some embodiments, the methods comprise combination therapy, wherein acompound, salt, and/or composition of the disclosure is co-administeredwith one or more additional therapeutic agents, such as, for example,another therapeutic agent used to treat hepatitis C (e.g., interferon orinterferon/ribavirin combination, or an HCV inhibitor such as, forexample, an HCV polymerase inhibitor an HCV protease inhibitor, an NS5ainhibitor). The compound, salts, and/or compositions of this disclosurecan also be co-administered with therapeutic agents other thantherapeutic agents used to treat hepatitis C (e.g., anti-HIV agents). Inthese co-administration embodiments, the compound, salts, and/orcompositions of the disclosure and the additional therapeutic agent(s)may be administered in a substantially simultaneous manner (e.g., orwithin about 5 minutes of each other), in a sequential manner, or both.It is contemplated that such combination therapies may includeadministering one therapeutic agent multiple times between theadministrations of the other. The time period between the administrationof each agent may range from a few seconds (or less) to several hours ordays, and will depend on, for example, the properties of eachcomposition and active ingredient (e.g., potency, solubility,bioavailability, half-life, and kinetic profile), as well as thecondition of the patient.

This disclosure also is directed, in part, to use of the disclosedcompounds, salts, and/or compositions, and, optionally one or moreadditional therapeutic agents to prepare a medicament. For example,compounds of formula (A) such asN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(compound (A-1)) made by disclosed processes can be used in themanufacture of a medicament.

In embodiments, the medicament is for co-administration with one or moreadditional therapeutic agents.

In embodiments, the medicament is for inhibiting replication of an RNAvirus such as HCV.

In embodiments, the medicament is for inhibiting HCV RNA polymerase.

In embodiments, the medicament is for treating hepatitis C.

This disclosure also is directed, in part, to the disclosed compounds,salts, and/or compositions, and, optionally one or more additionaltherapeutic agents, for use in inhibiting replication of an RNA virus,for inhibiting HCV RNA polymerase, or for treating hepatitis C.

EXAMPLES

The following examples are merely illustrative, and not limiting to thisdisclosure in any way.

Abbreviations which have been used in the descriptions of the Schemesand Examples that follow are: DMF for N,N-dimethylformamide; DMSO fordimethyl sulfoxide; HPLC for high performance liquid chromatography;LC-MS for liquid chromatographyl-mass spectrometry; Me for methyl; MeCNfor acetonitrile; pa % for peak area %; Pd₂dba₃ fortris(dibenzylideneacetone)dipalladium(0); THF for tetrahydrofuran; v/vfor volume/volume; wt for weight; w/w for weight/weight.

Certain reactions in the Examples below may have been analyzed usingreversed-phase HPLC. Analyses may have been conducted using areversed-phase amide column (Ascentis® Express RP-Amide, 100×4.6 mm ID,2.7 micron). Compounds may have been eluted using a gradient of about25-95% acetonitrile in 0.1% aqueous perchloric acid at a flow rate of1.9 mL/minute. One specific gradient starts with 25-44% acetonitrileover 12.5 minutes; 44-77% acetonitrile over 6 minutes; 77-95%acetonitrile over 1.5 minutes; hold at 95% acetonitrile for 3.5 minutes;95-25% acetonitrile over 0.01 minutes; and hold at 25% acetonitrile for3.99 minutes.

Example 1 Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (1c)) Part A Preparation of 2-tert-butyl-4,6-diiodophenol

2-tert-Butylphenol (99.95 g, 665.36 mmol) was dissolved in 1250 mLmethanol and converted to the corresponding phenoxide with 31.96 g(799.0 mmol, 1.2 equivalents) of sodium hydroxide by stirring the sodiumhydroxide pellets at room temperature, and then cooling the reactionmixture in an ice/salt bath. Sodium iodide (299.34 g, 1997.07 mmol, 3.0equivalents) and 8.3% bleach (1265.83 g, 1411.39 mmol, 2.1 equivalents)were added to the cold reaction solution in four equal portions, thebleach being added while keeping the reaction mixture at <0° C. 500 mLof 20% (w/w) sodium thiosulfate solution was added over an 18 minuteperiod, with the temperature rising from −0.6° C. to 2.5° C. The pH ofthe reaction mixture was adjusted to approximately 3 by adding 197.5 mLof concentrated HCl over a period of 97 minutes with the reactiontemperature going from 1.2° C. to 4.1° C. The resulting slurry wasfiltered, and the wet cake washed with approximately 2 L of water. Thewet cake was left on the Buchner funnel under vacuum overnight(approximately 15 hours) to yield 289.33 g (potency adjustedyield=254.61 g) of the title product.

Part B Preparation of 1-tert-butyl-3,5-diiodo-2-methoxybenzene

The product from Part A (93% assay, 21.6 g, 50 mmol) was dissolved in140 mL of acetone. Methyl iodide (4.2 mL, 67.5 mmol, 1.35 equivalents)was added, followed by 50% aqueous sodium hydroxide (5.0 g, 62.5 mmol,1.25 equivalents). The reaction was stirred overnight, then concentratedto approximately 50-60 mL. 80 mL of heptanes were added followed by 50mL of water, and the layers were shaken and separated, and the aqueouslayer was back extracted with 20 mL of heptanes. The organic layers werecombined and washed twice with 50 mL each of 10% aqueous NaCl to afford91.1 grams of a heptane solution, which assayed to 19.1 g of the titlecompound.

Part C Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

Uracil (33.3 g, 297 mmol, 1.2 equivalents), K₃PO₄ (106 g, 500 mmol, 2.1equivalents), CuI (4.6 g, 24.2 mmol, 0.1 equivalents), andN-(2-cyanophenyl)picolinamide (6.4 g, 28.7 mmol, 0.12 equivalents) werecharged to a flask, and the mixture was sparged with argon. The1-tert-butyl-3,5-diiodo-2-methoxybenzene was solvent switched intoacetonitrile, dissolved in 1 L dimethyl sulfoxide and sparged with argonand added to the solids. The reaction was heated to 60° C. for 16 hours.After cooling, the reaction was diluted with 2 L ethyl acetate andwashed with 2.6 L water (back extracted with 3×1 L ethyl acetate). Thecombined organic layers were washed with 2×1 L of 0.25 M copper(II)acetate then 2×830 mL of 15% NH₄Cl and then 800 mL of brine. The organiclayer was then concentrated, heptane (1 L) was added to the residue, andthe mixture was re-evaporated. The resulting residue was then trituratedwith refluxing 85:15 (v/v) heptane:isopropyl acetate for 4 hours. Aftercooling, the product was collected by filtration and washed with anadditional 330 mL of 85:15 v/v heptanes:ethyl acetate to yield afterdrying 66.9 g (70% yield) of the title compound as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.66 (s, 1H), 7.65 (d, J=2.6 Hz, 1H), 7.25 (dd,J=4.8, 3.2 Hz, 2H), 5.81 (dd, J=7.9, 2.0 Hz, 1H), 3.93 (s, 3H), 1.39 (s,9H).

Example 1-2 Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (1c))

Six reactions were set up as follows: A degassed solution of1-tert-butyl-3,5-diiodo-2-methoxybenzene (1.18 grams, 2.5 mmol) in 10 mLof dimethyl sulfoxide was degassed, then added to a vial containinguracil (336 mg, 3.0 mmol, 1.2 equiv.), N-(2-cyanophenyl)benzamide (67mg, 0.30 mmol, 0.12 equiv.), CuI (48 mg, 0.25 mmol, 0.10 equiv.) andpotassium phosphate (1.11 grams, 5.25 mmol, 2.1 equiv.). Three of thereactions also contained sodium ascorbate (20 mg, 0.10 mmol, 0.04equiv.).

The reactions were heated to 60° C. for 10 minutes, and then treated asfollows. Of the experiments without ascorbate, one was not furthertreated, one was treated with 2.5 mL of air, and one with 5 mL of air.Likewise, of the experiments with ascorbate, one was not furthertreated, one was treated with 2.5 mL of air, and one with 5 mL of air.Heating was continued at 60° C. for an additional 15 hours, thenanalyzed by HPLC. The table below indicates the effect of both air andsodium ascorbate on the course of the reaction.

Reaction Air added Ascorbate added Conversion 1 none none 82% 2 none0.04 equiv. 91% 3 2.5 mL none 74% 4 2.5 mL 0.04 equiv. 88% 5   5 mL none60% 6   5 mL 0.04 equiv. 82%

As seen in FIG. 1, reactions with ascorbate afford higher conversionthan corresponding reactions without the additive, and they are lesssensitive to the presence of air.

Example 2 Preparation of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (4a))

This reaction is sensitive to oxygen, and care was taken to establishand maintain an inert atmosphere in the handling and use ofair-sensitive materials or mixtures. All solution transfers wereaccomplished by cannula technique using nitrogen as the inert gas.Anhydrous tetrahydrofuran was sparged with nitrogen gas for 2 hoursprior to use to render it anaerobic. Hereafter this is referred to asdegassed tetrahydrofuran.

A 100-mL round-bottom flask was charged with 12.9 g of potassiumphosphate tribasic (60.8 mmol, 2.0 equivalents), a magnetic stir bar,and 60 mL of water. The mixture was stirred to dissolve the solids, andthe aqueous solution was sparged with nitrogen gas for 2 hours prior touse. Hereafter this is referred to as the phosphate solution.

A 100-mL round-bottom flask was purged with nitrogen gas and chargedwith 282 mg of tris(dibenzylideneacetone)dipalladium(0) (0.31 mmol, 0.02equivalents Pd), 413 mg of phosphine ligand,1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane(1.4 mmol, 2.3 equivalents relative to Pd) and a magnetic stir bar. Theflask was sealed with a septum and the atmosphere above the solids waspurged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was addedto the flask and the mixture was stirred under a nitrogen atmosphere.This solution was sparged with nitrogen for 15 minutes prior to use andis hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer andreflux condenser and the atmosphere was purged with nitrogen gas. Thereactor was charged with 12.1 g of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione,(30.3 mmol, 1.0 equivalent) and 5.98 g of6-hydroxynaphthalen-2-ylboronic acid (31.8 mmol, 1.05 equivalents). Theatmosphere was purged with nitrogen gas with stirring of the solidreagents for 20 minutes. The reactor was charged with 120 mL of degassedtetrahydrofuran, and the mixture was stirred to dissolve the solids. Thesolution was sparged with nitrogen gas for 10 minutes. The phosphatesolution was added to the reactor by cannula, followed by the catalystsolution. The resulting biphasic mixture was stirred aggressively toensure adequate phase mixing, and the jacket was warmed to 65° C. Thereaction jacket was cooled to room temperature prior to quench.

After 2.5 hours, the reaction jacket was cooled to room temperatureprior to quench.

The workup of the reaction was also conducted under anaerobicconditions. Fifty-seven grams of sodium chloride and 4.2 g of cysteine(15 weight equivalents relative to palladium catalyst) were dissolved in300 mL of water, and the resulting solution was sparged with inert gasfor 2 hours prior to use. To quench the reaction, approximately ⅓ ofthis solution was transferred to the reaction mixture by cannula undernitrogen gas and the resulting biphasic mixture was stirred vigorouslyfor 2 hours. The mechanical agitation was halted, the two solutions wereallowed to separate, and the aqueous solution was drained out of thereactor through the bottom valve. Approximately ⅓ of the quench solutionwas transferred to the reaction mixture by cannula under nitrogen gasand the resulting biphasic mixture was stirred vigorously for 45minutes. The mechanical agitation was halted, the two solutions wereallowed to separate, and the aqueous solution was drained out of thereactor through the bottom valve. The final portion of the quenchsolution was transferred to the reaction mixture by cannula, theresulting biphasic mixture was stirred vigorously for 45 minutes and theaqueous solution was drained out of the reactor through the bottomvalve.

The remainder of the workup was not conducted under anaerobicconditions. The pale yellow organic solution was drained from thereactor through the bottom valve and filtered over a pad of grade 4Filtrol® (1 cm deep by 4.5 cm diameter). The reactor and filter cakewere rinsed with 70 mL of tetrahydrofuran. The bulk of the solvent wasdistilled in vacuo (ca 90-130 torr) at ca 40° C. with good agitationfrom an overhead stirrer. The solution was concentrated to approximately50 mL volume, during which time the product began to precipitate out.Ethyl acetate (100 mL, about 8 mL of solvent per gram of the product)was added to the mixture, and the resultant slurry was stirred overnightat room temperature. The crystalline material was isolated by filtrationand the filter cake was washed twice with 20 mL portions of ethylacetate. The wet cake was air-dried on the filter and dried in a vacuumoven at 50° C. at approximately 250 torr with a gentle nitrogen sweepovernight.

The desired product was isolated as a white solid (11.6 g, 96.4% potencyvs. standard, 88% potency-adjusted yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.80(d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.32(d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.10(dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H), 3.23 (s, 3H),1.41 (s, 9H).

Example 2-1 Alternative Preparation of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (4a))

This reaction is air-sensitive and the reaction was conducted underanaerobic conditions. A 100-mL round-bottom flask was purged withnitrogen gas and charged with 229 mg oftris(dibenzylideneacetone)dipalladium(0) (0.25 mmol, 0.02 equivalentsPd), 323 mg of1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane(1.13 mmol, 0.045 equivalents) and a magnetic stir bar. The flask wassealed with a septum and the atmosphere above the solids was purged withnitrogen gas. Sixty mL of degassed tetrahydrofuran was added to theflask and the mixture was stirred under a nitrogen atmosphere for 20minutes. This solution is hereafter referred to as the catalystsolution.

A 500-mL jacketed reactor was equipped with an overhead stirrer andreflux condenser and the atmosphere was purged with nitrogen gas. Thereactor was charged with 10.0 g of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione,(25.1 mmol, 1.0 equivalent), 4.98 g of 6-hydroxynaphthalen-2-ylboronicacid (26.6 mmol, 1.06 equivalents) and 10.3 g of potassium phosphatetribasic (48.7 mmol, 2.0 equivalents). The atmosphere was purged withnitrogen gas with stirring of the solid reagents for 20 minutes. Thereactor was charged with 100 mL of tetrahydrofuran, 50 mL of water, andthe mixture was stirred to dissolve the solids. The biphasic mixture wassparged with nitrogen gas for 30 minutes. The catalyst solution wastransferred to the main reactor by positive nitrogen pressure through acannula. The resulting biphasic mixture was stirred aggressively andwarmed to an internal temperature between 60 and 65° C. under nitrogenfor 2 hours. The reaction mixture was cooled to an internal temperaturebetween 50 and 55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions atan internal temperature between 50 and 55° C. Fifteen grams of sodiumchloride and 1.0 g of cysteine were dissolved in 80 mL of water, and theresulting solution was sparged for 1 hour. This solution was transferredto the reaction mixture by cannula with nitrogen gas pressure and theresulting biphasic mixture was stirred vigorously for 45 minutes. Themechanical agitation was halted, the two solutions were allowed toseparate, and the aqueous solution was drained out of the reactorthrough the bottom valve. Fifteen grams of sodium chloride and 1.0 g ofcysteine were dissolved in 80 mL of water, and the resulting solutionwas sparged for 1 hour. This solution was transferred to the reactionmixture by cannula with nitrogen gas pressure and the resulting biphasicmixture was stirred vigorously for 45 minutes. The mechanical agitationwas halted, the two solutions were allowed to separate, and the aqueoussolution was drained out of the reactor through the bottom valve.

The pale yellow organic solution was drained from the reactor throughthe bottom valve and filtered over a polypropylene filter to removepalladium black. The reactor and filter cake were rinsed with 22 mL oftetrahydrofuran and 50 mL of ethyl acetate was added to the organicsolution. The solution was distilled at atmospheric pressure(approximately 66° C. internal temperature) with continuous addition of110 mL of ethyl acetate, keeping the volume of the solution roughlyconstant during the distillation. During the constant-volumedistillation, solids began to precipitate in the reactor. After theethyl acetate was charged, the distillation was continued at atmosphericpressure, concentrating the slurry to approximately 60 mL total volume.The solution was cooled to an internal temperature of approximately 30°C. and held for 3 hours with stirring. The crystalline material wasisolated by filtration and the filter cake was washed twice with 20 mLportions of ethyl acetate. The wet cake was dried in a vacuum oven at50° C. with a gentle nitrogen sweep overnight. The desired product wasisolated as an off-white solid (8.33 g, 80% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm δ 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3Hz, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H),3.23 (s, 3H), 1.41 (s, 9H).

Example 2-2 Alternative Preparation of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(Compound (4a))

This reaction is air-sensitive and the reaction was conducted undernitrogen atmosphere. A 100-mL round-bottom flask was purged withnitrogen gas and charged with 303 mg oftris(dibenzylideneacetone)dipalladium(0) (0.33 mmol, 0.02 equivalentsPd), 411 mg of1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane(1.40 mmol, 0.045 equivalents) and a magnetic stir bar. The flask wassealed with a septum and the atmosphere above the solids was purged withnitrogen gas. Seventy-five (75) mL of degassed tetrahydrofuran was addedto the flask and the mixture was stirred under a nitrogen atmosphere for25 minutes. This solution is hereafter referred to as the catalystsolution.

A 500-mL jacketed reactor was equipped with an overhead stirrer andreflux condenser and the atmosphere was purged with nitrogen gas. Thereactor was charged with 12.5 g of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione,(31.2 mmol, 1.0 equivalent), 6.20 g of 6-hydroxynaphthalen-2-ylboronicacid (33.0 mmol, 1.06 equivalents) and 13.0 g of potassium phosphatetribasic (61.2 mmol, 2.0 equivalents). The reactor was charged with 130mL of tetrahydrofuran, 65 mL of water, and the mixture was stirred todissolve the solids. The biphasic mixture was sparged with nitrogen gasfor 30 minutes. The catalyst solution was transferred to the mainreactor by positive nitrogen pressure through a cannula. The resultingbiphasic mixture was stirred aggressively and warmed to an internaltemperature between 60 and 65° C. under nitrogen for 2.5 hours. Thereaction mixture was cooled to an internal temperature between 50 and55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions atan internal temperature between 50 and 55° C. Sodium chloride (18.8 g)and cysteine (1.25 g) were dissolved in 100 mL of water, and theresulting solution was sparged with nitrogen for 40 minutes. Thissolution was transferred to the reaction mixture by cannula withnitrogen gas pressure and the resulting biphasic mixture was stirredvigorously for 45 minutes. The mechanical agitation was halted, the twosolutions were allowed to separate, and the aqueous solution was drainedout of the reactor through the bottom valve. Sixty-three (63) mL ofdegassed tetrahydrofuran were added to the reactor by cannula withpositive nitrogen pressure. Sodium chloride (18.9 g) and cysteine (1.333g) were dissolved in 100 mL of water, and the resulting solution wassparged with nitrogen for 40 minutes. This solution was transferred tothe reaction mixture by cannula with nitrogen gas pressure and theresulting biphasic mixture was stirred vigorously for 45 minutes. Themechanical agitation was halted, the two solutions were allowed toseparate, and the aqueous solution was drained out of the reactorthrough the bottom valve.

The pale yellow organic solution was drained from the reactor throughthe bottom valve and filtered through a thin pad of filter aid on apolyethylene filter while warm. The reactor and filter cake were rinsedwith 32 mL of tetrahydrofuran, and 65 mL of ethyl acetate was added tothe organic solution. The solution was distilled at atmospheric pressure(approximately 66° C. internal temperature) with continuous addition of190 mL of ethyl acetate, keeping the volume of the solution roughlyconstant during the distillation. During the constant-volumedistillation, solids began to precipitate in the reactor. After theethyl acetate was charged, the distillation was continued at atmosphericpressure, concentrating the slurry to approximately 90 mL total volume.The slurry was cooled to an internal temperature of approximately 40° C.and was concentrated further in vacuo to a total volume of approximately50 mL. The slurry was cooled to an internal temperature of 30° C. andheld for 16 hours with stirring. The crystalline material was isolatedby filtration, and the filter cake was washed twice with 25 mL portionsof ethyl acetate. The wet cake was dried in a vacuum oven at 50° C. witha gentle nitrogen sweep overnight. The desired product was isolated asan off-white solid (11.4 g, 99.5% potent vs. standard, 87%potency-adjusted yield).

Example 3 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Compound (5a))

A reactor was equipped with an overhead stirrer in the central neck andcharged with 45.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(97.8 weight %, 106 mmol, 1.0 equivalent) and 21.9 g of 325 meshpotassium carbonate (159 mmol, 1.5 equivalents). The atmosphere waspurged with nitrogen gas while the solids were stirred. The flask wascharged with 445 mL of N,N-dimethylformamide, and the slurry was stirredto dissolve the1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.The purge was stopped and the reaction was conducted under a slightpositive pressure of nitrogen gas. Perfluorobutanesulfonyl fluoride(35.2 g, 117 mmol, 1.1 equivalents) was added in one portion, and themixture was stirred vigorously to mix the immiscible liquids overnight.

The inorganic solids were separated by filtration, and the flask andfilter cake were rinsed with approximately 30 mL ofN,N-dimethylformamide. The N,N-dimethylformamide solution was filtereddirectly into a second flask with an overhead stirrer. With stirring,112 g of water (25 weight % of total N,N-dimethylformamide employed) wasadded to the N,N-dimethylformamide solution of product overapproximately 0.5 hour to induce precipitation of the desired product,and the mixture was allowed to stir for 5 hours. The wet cake wasisolated by filtration with recirculation of the liquors to recover allthe solids. The wet cake was washed with 60 mL of 25% (v/v)water/N,N-dimethylformamide, then 85 mL water.

The solids were dissolved in 760 mL of isopropyl acetate. The resultantorganic solution was washed once with 200 mL of water, twice with 270 mLportions of water and once with 200 mL of water to remove residualN,N-dimethylformamide. Solvent was removed by distillation atapproximately 130 torr with heating to 55° C. until the total volume wasapproximately 200 mL. With efficient stirring, heptane (450 mL) wasadded to the warm (55° C.) slurry. The slurry was allowed to cool toroom temperature overnight with stirring. The desired product wasisolated by filtration, with recycling of the liquors to isolate all ofthe solids material. The wet cake was washed twice with 100 mL portionsof 20% (v/v) isopropyl acetate/heptane. The wet cake was air-dried onthe filter and dried in a vacuum oven at 50° C. at approximately 250torr with a gentle nitrogen sweep overnight. The title compound wasisolated as a white solid (64.0 g, 87% yield). ¹H NMR (600 MHz, DMSO-d₆)δ ppm 11.42 (s, 1H), 8.21-8.15 (m, 4H), 7.84 (dd, J=8.6, 1.7 Hz, 1H),7.77 (d, J=7.9 Hz, 1H), 7.60 (dd, J=9.0, 2.5 Hz, 1H), 7.39 (d, J=2.7 Hz,1H), 7.35 (d, J=2.7 Hz, 1H), 5.66 (d, J=7.9 Hz, 1H), 3.21 (s, 3H), 1.41(s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ ppm 163.7, 156.7, 150.6, 147.1,145.7, 143.6, 137.4, 134.2, 134.1, 132.3, 132.1, 131.3, 128.5, 128.4,128.1, 127.2, 125.2, 120.0, 119.2, 101.4, 60.5, 35.0, 30.4; ¹⁹F NMR (564MHz, DMSO-d₆) δ ppm −79.9 (3F), −109.9 (2F), −120.7 (2F), −125.4 (2F).

Example 3-1 Alternative Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Compound (5a))

A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer wascharged with 10 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(98 wt %, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate(325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 mL pergram of naphthol) and N,N-dimethylformamide (DMF, 40 mL, 4 mL per gramof naphthol) was charged to the reactor and the slurry was stirred.Perfluorobutanesulfonyl fluoride (8.3 g, 26 mmol, 1.1 equiv) was chargedto the well-stirred mixture over 60 minutes by syringe pump. A trace(<0.1 area %) of starting material was detected by HPLC analysis of analiquot after 20 minutes of reaction time. Theacetonitrile/dimethylformamide solution was filtered over a coarsefitted funnel to separate the inorganic solids, and the flask and filterwas rinsed with 15 mL of 3:2 (v/v) acetonitrile/dimethylformamide. Thetotal mass of solvents employed was approximately 92 g.

First Crystallization:

The acetonitrile/dimethylformamide solution was transferred to a 3-neckflask equipped with an overhead stirrer. Water (50 g, 54 wt % withrespect to total solution charged) was added to the well-stirredsolution over 100 minutes. This adjusts the solvent composition to 35 wt% water. During the addition of water the mixture self-seeded, and thesolution was held for approximately 1 hour after complete addition ofwater. The solids were isolated by filtration, and the wet cake waswashed with two 30 mL portions of a rinse solution of 40 wt % water/27wt % dimethylformamide/33 wt % acetonitrile and then once with 40 mL ofwater.

Aqueous Washing:

A 500-L jacketed cylindrical reactor equipped with an overhead stirrerand polytetrafluoroethylene (PTFE) baffle to aid in vertical mixing wascharged with the wet cake and 133 g of ethyl acetate (8× theoreticalmass of product, 150 mL). The mixture was stirred to dissolve thesubstrate and the solution was washed twice with 40 mL portions ofwater.

Concentration and Crystallization:

A constant-volume distillation was conducted with heptanes, in vacuo (ca100 mmHg, jacket temperature of 50° C.), to adjust the solventcomposition to approximately 12 wt % ethyl acetate/88 wt % heptanes.During the distillation, solids begin to crystallize out of thesolution. Once the distillation was complete, the solution was cooled toambient temperature (23° C.). The solids were isolated by filtration andthe wet cake was washed with a 50-mL portions heptane. The wet cake wasdried to give the final product (14.0 g). The solids were 98.1% pure byHPLC analysis and 100% potent vs. reference standard, for an isolatedyield of 85%.

Example 3-2 Alternative Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Compound (5a))

A reactor was equipped with an overhead stirrer and charged with 8.04 gof1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(19.2 mmol, 1.0 equivalent) and 5.28 g of 325-mesh potassium carbonate(38.4 mmol, 2.0 equivalents). The flask was charged with 33 mL ofN,N-dimethylformamide and 51 mL of acetonitrile and the slurry wasstirred. Perfluorobutanesulfonyl fluoride (7.16 g, 23.7 mmol, 1.2equivalents) was added over 1.5 hours, and the mixture was stirred foran hour. The inorganic solids were separated by filtration, and theflask and filter cake were rinsed with a mixture of 4.8 mL ofN,N-dimethylformamide and 7.2 mL of acetonitrile. With stirring, 6.0 gof water was added to the organic solution and the mixture was allowedto stir for 30 minutes to allow solids to crystallize. An additional 34mL of water was added to the slurry over 1 hour, and the mixture wasallowed to stir for 2 hours. The wet cake was isolated by filtrationwith recirculation of the liquors to recover all the solids. The wetcake was washed with a pre-mixed solution of 6.5 mL ofN,N-dimethylformamide, 8.0 mL of acetonitrile and 9.5 mL of water.

The wet cake was dissolved in 65 mL of ethyl acetate. The resultantorganic solution was washed twice with 33 mL portions of a 5 wt %aqueous sodium chloride solution. The organic solution was filtered intoa reactor and the filter rinsed with 25 mL of ethyl acetate. The bulk ofthe solvent was removed by distillation at approximately 90 torr withheating to 40° C. until the total volume was approximately 25 mL. Theslurry was heated to 53° C. and 10 mL of ethyl acetate was added tocompletely dissolve the precipitated solids. Heptanes (125 mL) wereadded to the warm (55° C.) slurry over 40 minutes. The mixture wascooled to room temperature over an hour with stirring and the slurry wasstirred at ambient temperature for 17 hours. The desired product wasisolated by filtration, with recycling of the liquors to isolate all ofthe solids material. The wet cake was washed with 22 mL of heptanes. Thewet cake was dried in a vacuum oven at 50° C. with a gentle nitrogensweep. The title compound was isolated as a white solid (10.4 g, 77%yield). ¹H NMR (600 MHz, DMSO-d₆) δ ppm 11.42 (s, 1H), 8.21-8.15 (m,4H), 7.84 (dd, J=8.6, 1.7 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.60 (dd,J=9.0, 2.5 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.35 (d, J=2.7 Hz, 1H), 5.66(d, J=7.9 Hz, 1H), 3.21 (s, 3H), 1.41 (s, 9H).

Example 3-3 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,-heptafluoropropane-1-sulfonate (Compound (5b))

To a stirred solution of 6.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(14.4 mmol, 1.0 equivalent) in 60 mL of N,N-dimethylformamide was added4.0 g of 325-mesh potassium carbonate (29 mmol, 2.0 equivalents).1,1,2,2,3,3,3-heptafluoropropane-1-sulfonyl fluoride (3.85 g, 15.3 mmol,1.06 equivalents) was added over 20 minutes, and the mixture was stirredfor 3 hours. The inorganic solids were separated by filtration, and theflask and filter cake were rinsed with 75 mL of ethyl acetate. Thesolution was diluted with an additional 75 mL of ethyl acetate and theresultant solution was washed four times with 50 mL portions of 10 wt %aqueous sodium chloride, followed by 50 mL of saturated aqueous sodiumchloride solution. The organic solution was dried over sodium sulfate,the drying agent was filtered off and the organic solution wasconcentrated in vacuo. The resultant oil was dissolved in 5.8 mL ofethyl acetate and 90 mL of heptanes was added over 25 minutes. Theproduct crystallized and was isolated by filtration. The wet cake waswashed with 20 mL of heptanes and dried in vacuo with heating at 50° C.The title compound was isolated as a white solid (8.43 g, 90% yield). ¹HNMR (400 MHz, CDCl₃) δ ppm 8.66 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=9.5Hz, 1H), 7.93 (d, J=9.1 Hz, 1H), 7.83 (dd, J=8.5, 1.7 Hz, 1H), 7.79 (d,J=2.4 Hz, 1H), 7.41 (dd, J=8.9, 2.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H),7.27-7.24 (m, 2H), 5.82 (dd, J=7.9, 2.2 Hz, 1H), 3.30 (s, 3H), 1.46 (s,9H). ¹⁹C NMR (101 MHz, CDCl₃) δ ppm 162.6 (C), 157.5 (C), 149.9 (C),147.2 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.2(C), 132.2 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4 (CH), 127.2(CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 60.9 (CH₃), 35.8(C), 30.8 (CH₃). ¹⁹F NMR (564 MHz, DMSO-d₆) δ ppm −79.9 (3F), −109.9(2F), −124.0 (2F). LC-MS m/z 649.1 [M+H]⁺.

Example 3-4 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (Compound (5c))

To a stirred solution of 6.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(14.4 mmol, 1.0 equivalent) in 60 mL of N,N-dimethylformamide was added4.0 g of 325-mesh potassium carbonate (29 mmol, 2.0 equivalents).1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride (3.6 g, 14.3 mmol,1.0 equivalents) was added over 30 minutes, and the mixture was stirredfor 2 hours. An additional portion of1,1,1,2,3,3,3-heptafluoropropane-2-sulfonyl fluoride (0.21 g, 0.83 mmol,0.06 equivalents) was added, and the mixture was stirred for 1.5 hours.The inorganic solids were separated by filtration, and the flask andfilter cake were rinsed with 75 mL of ethyl acetate. The solution wasdiluted with an additional 75 mL of ethyl acetate and the resultantsolution was washed four times with 50 mL portions of 10 wt % aqueoussodium chloride, followed by 50 mL of saturated aqueous sodium chloridesolution. The organic solution was dried over sodium sulfate, the dryingagent was filtered off and the organic solution was concentrated invacuo. The resultant oil was dissolved in 7 mL of ethyl acetate, whichresulted in crystallization after stirring for a few minutes. Heptanes(90 mL) were added slowly to the stirred mixture. The product wasisolated by filtration, washed with 20 mL of heptanes and dried in vacuowith heating at 50° C. The title compound was isolated as a white solid(8.30 g, 89% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.05 (s, 1H), 7.95(d, J=9.6 Hz, 1H), 7.93 (d, J=9.6 Hz, 1H), 7.83 (dd, J=8.5, 1.7 Hz, 1H),7.78 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.9, 2.4 Hz, 1H), 7.36 (d, J=7.9 Hz,1H), 7.27-7.23 (m, 2H), 5.81 (d, J=7.9 Hz, 1H), 3.29 (s, 3H), 1.46 (s,9H) (NH not observed in this spectrum). ¹³C NMR (101 MHz, CDCl₃) δ ppm162.7 (C), 157.5 (C), 149.8 (C), 146.9 (C), 145.0 (C), 144.5 (CH), 137.2(C), 135.1 (C), 133.0 (C), 132.2 (C), 132.2 (C), 130.5 (CH), 128.5 (CH),128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH),102.4 (CH), 60.9 (CH₃), 35.8 (C), 30.8 (CH₃). ¹⁹F NMR (564 MHz, DMSO) δppm −71.08 (6F), −167.87 (1F). LC-MS m/z 649.1 [M+H]⁺.

Example 3-5 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,2-pentafluoroethanesulfonate (Compound (5d))

To a stirred solution of 10.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(23.5 mmol, 1.0 equivalent) in 100 mL of N,N-dimethylformamide was added6.5 g of 325-mesh potassium carbonate (47 mmol, 2.0 equivalents).1,1,2,2,2-pentafluoroethanesulfonyl fluoride (4 g, 20 mmol, 0.85equivalents) was bubbled sub-surface into the reaction mixture over 3hours, and the mixture was stirred for 0.5 hours. The inorganic solidswere separated by filtration, and the flask and filter cake were rinsedwith 5 mL of N,N-dimethylformamide. The solution was diluted with 24 mLof water and 150 mL of ethyl acetate and the resultant solution waswashed four times with 50 mL portions of 10 wt % aqueous sodiumchloride, followed by 25 mL of saturated aqueous sodium chloridesolution. The organic solution was dried over sodium sulfate, the dryingagent was filtered off and the organic solution was concentrated invacuo. The resultant solid was purified by chromatography over silicagel with gradient elution (40% ethyl acetate/hexanes to 60% ethylacetate/hexanes). The desired product was dissolved in 10 mL of ethylacetate and 200 mL of heptanes was added over 60 minutes. The productcrystallized and was isolated by filtration. The wet cake was washedwith 40 mL of heptanes and dried in vacuo with heating at 50° C. Thetitle compound was isolated as a white solid (9.4 g, 67% yield). ¹H NMR(600 MHz, CDCl₃) δ ppm 8.60 (d, J=0.5 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H),7.97 (d, J=9.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz,1H), 7.80 (d; J=2.5 Hz, 1H), 7.42 (dd, J=9.0, 2.5 Hz, 1H), 7.37 (d,J=8.0 Hz, 1H), 7.27-7.26 (m, 2H), 5.82 (dd, J=8.0, 2.3 Hz, 1H), 3.30 (s,3H), 1.46 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 162.6 (C), 157.5 (C),149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0(C), 132.23 (C), 132.18 (C), 130.5 (CH), 128.5 (CH), 128.1 (CH), 127.4(CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 61.0(CH₃), 35.8 (C), 30.8 (CH₃). ¹⁹F NMR (564 MHz, CDCl₃) δ ppm −79.1 (3F),−113.4 (2F). LC-MS m/z 599.1 [M+H]⁺.

Example 3-6 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yltrifluoromethanesulfonate (Compound (5e))

To a stirred solution of 9.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(21.1 mmol, 1.0 equivalent) in 90 mL of N,N-dimethylformamide was added5.9 g of 325-mesh potassium carbonate (42.8 mmol, 2.0 equivalents).Trifluoromethanesulfonyl fluoride was bubbled sub-surface into thereaction mixture slowly over 1 hour until the starting material was nolonger detected by HPLC. The inorganic solids were separated byfiltration, and the flask and filter cake were rinsed with 50 mL ofethyl acetate. The solution was diluted with 50 mL of ethyl acetate andthe resultant solution was washed three times with 50 mL portions of 10wt % aqueous sodium chloride, followed by 50 mL of saturated aqueoussodium chloride solution. The organic solution was dried over sodiumsulfate, the drying agent was filtered off and the organic solution wasconcentrated in vacuo. The resultant oil was solidified by adding 70 mLof 10% ethyl acetate/heptanes and holding for 16 hours. The product wasisolated by filtration. The wet cake was washed with 25 mL of 10% ethylacetate/heptanes and dried in vacuo with heating at 50° C. The titlecompound was isolated as a white solid (10.8 g, 93% yield). ¹H NMR (600MHz, CDCl₃) δ ppm 8.63 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.97 (d, J=9.1Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.84 (dd, J=8.5, 1.7 Hz, 1H), 7.79 (d,J=2.5 Hz, 1H), 7.41 (dd, J=9.0, 2.5 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H),7.27-7.26 (m, 2H), 5.82 (dd, J=7.9, 2.3 Hz, 1H), 3.30 (s, 3H), 1.46 (s,9H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 162.7 (C), 157.5 (C), 149.9 (C),147.0 (C), 145.0 (C), 144.5 (CH), 137.2 (C), 135.1 (C), 133.0 (C), 132.24 (C), 132.19 (C), 130.5 (CH), 128.5 (CH), 128.0 (CH), 127.4 (CH), 127.2(CH), 124.4 (CH), 119.9 (CH), 118.9 (CH), 102.4 (CH), 61.0 (CH₃), 35.8(C), 30.8 (CH₃). ¹⁹F NMR (564 MHz, CDCl₃) δ ppm −72.8 (3F). LC-MS m/z549.2 [M+H]⁺.

Example 3-7 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (Compound (5f))

To a stirred solution of 0.53 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(1.27 mmol, 1.0 equivalent) in 5 mL of N,N-dimethylformamide was added0.35 g of 325-mesh potassium carbonate (2.6 mmol, 2.0 equivalents).Perfluoro(2-ethoxyethane)sulfonyl fluoride (0.46 g, 1.4 mmol, 1.1equivalents) was added in one portion, and the mixture was stirred foran hour. The inorganic solids were separated by filtration, and theflask and filter cake were rinsed with 1 mL of N,N-dimethylformamidefollowed by 2 mL of ethyl acetate. The solution was diluted with 30 mLof ethyl acetate and the resultant solution was washed twice with 20 mLportions of 10 wt % aqueous sodium chloride, followed by 20 mL ofsaturated aqueous sodium chloride solution. The washing procedure wasrepeated once. The organic solution was dried over sodium sulfate, thedrying agent was filtered off and the organic solution was concentratedin vacuo. The resultant solid was purified by chromatography over silicagel with gradient elution (30% ethyl acetate/hexanes to 60% ethylacetate/hexanes). The title compound was isolated as a white solid (0.76g, 84% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.54 (d, J=1.7 Hz, 1H),8.04 (s, 1H), 7.95 (d, J=9.4 Hz, 1H), 7.92 (d, J=10.1 Hz, 1H), 7.83 (dd,J=8.5, 1.7 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.40 (dd, J=9.0, 2.5 Hz,1H), 7.36 (d, J=7.9 Hz, 1H), 7.27-7.23 (m, 2H), 5.81 (dd, J=7.9, 2.4 Hz,1H), 3.29 (s, 3H), 1.46 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 162.6(C), 157.5 (C), 149.8 (C), 147.1 (C), 145.0 (C), 144.5 (CH), 137.2 (C),135.1 (C), 133.0 (C), 132.2 (C), 132.2 (C), 130.5 (CH), 128.5 (CH),128.1 (CH), 127.4 (CH), 127.2 (CH), 124.4 (CH), 119.9 (CH), 118.9 (CH),102.4 (CH), 60.9 (CH₃), 35.8 (C), 30.8 (CH₃). ¹⁹F NMR (564 MHz, CDCl₃) δppm −81.61 (2F), −86.42 (3F), −88.11 (2F), −112.90 (2F). LC-MS m/z 715.0[M+H]⁺.

Example 3-8 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylsulfofluoridate (Compound (5g))

To a stirred solution of 5.1 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(12.2 mmol, 1.0 equivalent) in 50 mL of N,N-dimethylformamide at ambienttemperature was added 3.3 g of 325-mesh potassium carbonate (24 mmol,2.0 equivalents). The reaction flask was equipped with a dry ice/acetonecondenser and sulfuryl fluoride was bubbled sub-surface into thereaction mixture slowly over 10 minutes. HPLC analysis at that timeindicated no starting material remained. The mixture was allowed to stirfor an additional 1 hour. The solution was sparged sub-surface withnitrogen gas to purge any residual sulfuryl fluoride from the reactor,and the inorganic solids were separated by filtration. The DMF solutionwas diluted with 125 mL of ethyl acetate and the resultant solution waswashed four times with 50 mL portions of 10 wt % aqueous sodiumchloride, followed by 50 mL of saturated aqueous sodium chloridesolution. The organic solution was dried over sodium sulfate, the dryingagent was filtered off and the organic solution was concentrated invacuo. The resultant oil was crystallized by adding 2 mL of ethylacetate, followed by 75 mL of heptanes slowly over several hours. Theresultant slurry was mixed for 16 hours, and the product was isolated byfiltration. The wet cake was washed with heptanes and dried in vacuowith heating at 50° C. The title compound was isolated as a white solid(5.7 g, 95% yield). ¹H NMR (600 MHz, DMSO-d₆) δ ppm 11.40 (d, J=2.0 Hz,1H), 8.29 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 2H), 8.18 (d, J=8.6 Hz, 1H),7.87 (dd, J=8.6, 1.7 Hz, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.75 (dd, J=9.1,2.5 Hz, 1H), 7.41 (d, J=2.7 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 5.66 (dd,J=7.9, 2.3 Hz, 1H), 3.24 (s, 3H), 1.43 (s, 9H). ¹³C NMR (101 MHz,DMSO-d₆) δ ppm 163.0 (C), 156.0 (C), 149.9 (C), 146.9 (C), 145.2 (CH),143.0 (C), 136.9 (C), 133.7 (C), 133.6 (C), 131.9 (C), 131.6 (C), 130.9(CH), 128.1 (CH), 128.0 (CH), 127.6 (CH), 126.8 (CH), 124.8 (CH), 119.2(CH), 118.4 (CH), 101.1 (CH), 60.5 (CH₃), 35.1 (C), 30.5 (CH₃). ¹⁹F NMR(564 MHz, DMSO-d₆) δ ppm 38.9 (F). LC-MS m/z 499.15 [M+H]⁺.

Example 3-9 Preparation of6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylmethanesulfonate (Compound (5h))

To a stirred slurry of 5.0 g of1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione(12.0 mmol, 1.0 equivalent) in 25 mL of N,N-dimethylacetamide was added4.4 g of methanesulfonic anhydride (25 mmol, 2.1 equivalents). Thesolution was cooled in a water bath to keep the internal temperaturebelow 30° C. during the addition of 8.5 mL of triethylamine (61 mmol,5.1 equivalents). After stirring for 2.5 hours at room temperature, anadditional 0.70 g of methanesulfonic anhydride (4 mmol, 0.3 equiv) wasadded to the mixture. The reaction mixture was quenched by the additionof 30 mL of water with stirring. The resultant heterogeneous mixture wasdissolved in 150 mL of ethyl acetate, and the resultant solution waswashed five times with 50 mL portions of 10 wt % aqueous sodiumchloride. The organic solution was dried over sodium sulfate, the dryingagent was filtered off and the organic solution was concentrated invacuo. The resultant oil was solidified by holding in a refrigerator andpurified by slurrying in 20 mL of ethyl acetate. The product wasisolated by filtration, the wet cake was washed with ethyl acetate anddried in vacuo with heating at 50° C. The title compound was isolated asa white solid (4.5 g, 91% potent, 69% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 11.36 (d, J=1.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d, J=9.1 Hz, 1H),8.05 (d, J=8.7 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.79-7.72 (m, 2H), 7.49(dd, J=8.9, 2.4 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H),5.61 (dd, J=7.9, 1.9 Hz, 1H), 3.43 (s, 3H), 3.20 (s, 3H), 1.39 (s, 9H).¹³C NMR (101 MHz, DMSO-d₆) δ ppm 163.0 (C), 156.0 (C), 150.0 (C), 146.4(C), 145.2 (CH), 143.0 (C), 135.9 (C), 134.0 (C), 133.6 (C), 131.9 (C),131.3 (C), 130.0 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 126.7 (CH),124.6 (CH), 121.3 (CH), 119.0 (CH), 101.1 (CH), 60.4 (CH₃), 37.6 (CH₃),35.1 (C), 30.5 (CH₃). LC-MS m/z 495.1 [M+H]⁺.

Example 4 Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 3-L, 3-neck, round-bottom flask was equipped with an overhead stirrer,a thermocouple, a Claisen condenser and a reflux condenser.Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine(0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g,99.0 mmol) were charged to the 3-L flask. The flask was purged withargon for not less than 90 minutes with constant stirring of the solids.t-Amyl alcohol (250 ml) was charged to a separate 500-mL round-bottomflask and was purged with argon for not less than 30 minutes and wastransferred to the 3-L flask using a cannula under argon atmosphere. Thecontents of the 3-L flask were heated to 80° C. and stirred at thistemperature for 30 minutes. A 1-L round-bottom flask equipped with amagnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (62.9 g, 90 mmol),methanesulfonamide (12.85 g, 135 mmol) and t-amyl alcohol (505 mL),purged with argon and heated to 60° C. The reagent mixture was stirredunder argon for not less than 30 minutes. A clear yellow solution wasobserved. This solution was transferred to the 3-L flask using a cannulaunder argon atmosphere. The temperature of the 3-L flask was raised to85° C. and the contents were stirred for 14 hours under a positivepressure of argon. The temperature was then raised to 95° C. and thecontents were stirred for an additional 4 hours under a positivepressure of argon. The reaction mixture was allowed to cool down to roomtemperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL)and was transferred to a 6-L separatory funnel. The organic layer waswashed thrice with water (2000 mL) containing L-cysteine (17.3 g) andNaCl (235 g). The organic layer was collected, filtered through a pad ofdiatomaceous earth and was concentrated in vacuo to approximately 250mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and themixture was allowed to stir for an additional 14 hours. White solid wasisolated by filtration, and the solid was washed with ethyl acetate(1000 mL). The solid was then dissolved in tetrahydrofuran (1500 mL) andfiltered through a pad of diatomaceous earth to obtain a clear solution.The diatomaceous earth was washed with tetrahydrofuran (300 mL). Thecombined tetrahydrofuran solution was concentrated in vacuo toapproximately 250 mL, and then ethyl acetate (775 mL) was added over 7hours with stirring. The product solution was allowed to stir for anadditional 14 hours. White solid was isolated by filtration. The solidwas washed with ethyl acetate (1000 mL) and dried in a vacuum oven at60° C. for 24 hours. The solid was slurried in 308 mL of 200 proofethanol for 1.5 hours, then isolated by filtration. The solid was washedwith 132 mL of 200 proof ethanol and dried in a vacuum oven at 50° C.for 18 hours. The title compound was isolated as a white solid (32.6 g,100% potency vs. standard, 73% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.41 (d, J=2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J=0.9 Hz, 1H),7.98-7.91 (m, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.69(dd, J=8.5, 1.7 Hz, 1H), 7.41 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=2.7Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 5.65 (dd, J=7.9, 2.2 Hz, 1H), 3.24 (s,3H), 3.08 (s, 3H), 1.42 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 163.1(C), 156.0 (C), 150.0 (C), 145.3 (CH), 142.9 (C), 136.0 (C), 134.3 (C),134.2 (C), 133.5 (C), 132.2 (C), 129.5 (C), 129.0 (CH), 127.6 (CH),127.1 (CH), 127.0 (CH), 126.5 (CH), 124.3 (CH), 120.2 (CH), 114.5 (CH),101.1 (CH), 60.3 (CH₃), 39.4 (CH₃), 35.1 (C), 30.5 (CH₃).

Other ligands such as2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane;7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane;and8-(2-(2-methoxynaphthalen-1-yl)phenyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decanewere tested under the conditions described above and produced favorableyields of greater than 50% of the sulfonamidated product.

TABLE 1 Alternative Ligands for Sulfonamidation Pd (mol %) Ligand (mol%) 17,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2) 12,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane(1.2)8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane (1.2) 12,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-ol(1.2) 18-(2′,6′-diisopropoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2) 11,3,5,7-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane (1.2) 18-(2′,6′-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane 16-methoxy-N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine (1.2) 18-(2′-methoxy-1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2) 18-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2) 17,7,9,9-tetramethyl-8-(2-(naphthalen-1-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2) 17,7,9,9-tetramethyl-8-(2-(naphthalen-2-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane (1.2)

Example 4-1 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with anoverhead stirrer was charged withtris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.167 g, 0.344 mmol) and milled potassium phosphate tribasic (6.69 g,31.5 mmol). The flask was purged with argon for not less than 90minutes. Tetrahydrofuran (90 mL) was taken in a 100-mL round bottomflask, purged with argon for not less than 30 minutes and wastransferred to the 450-mL reactor using a cannula under argonatmosphere. The contents of the 450-mL reactor were heated to 80° C. andstirred at this temperature for 30 minutes. A 250-mL, round-bottom flaskequipped with a magnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (20.0 g, 28.6 mmol),methanesulfonamide (3.27 g, 34.4 mmol) and tetrahydrofuran (160 mL),purged with argon for not less than 45 minutes. A clear yellow solutionwas observed. This solution was transferred to the 450-mL reactor thathas been cooled to the room temperature using a cannula under argonatmosphere. The temperature of the 450-mL reactor was raised to 90° C.and the contents were stirred for 20 hours. The reaction mixture wasallowed to cool down to 50° C., diluted with tetrahydrofuran (70 mL) andwater (70 mL) containing L-cysteine (0.875 g) and sodium chloride (7.7g). The contents were stirred for 2 hours at 50° C. The aqueous layerwas discarded and the organic layer was filtered through anapproximately 2-inch pad of diatomaceous earth and rinsed withtetrahydrofuran (45 mL) to obtain a clear, light yellow solution. Thetotal weight of reaction mixture was 363.43 g. HPLC analysis of thereaction mixture revealed 13.71 g (97%) of the title compound waspresent in the reaction mixture. A portion of the reaction mixture (50g) was concentrated to a final volume of 12-14 mL under vacuum. Ethylacetate (45 mL) was added slowly and the reaction mixture was stirredover night at room temperature to obtain white slurry. Product wascollected by filtration, washed with ethyl acetate (7 mL) and driedovernight in a vacuum oven at 50-60° C. to obtain 2.02 g of white solid.Ethanol (14 mL) was added to the solid and stirred overnight at the roomtemperature. The product was collected by filtration, washed withethanol (4 mL) and dried overnight in a vacuum oven at 50-60° C. toobtain the title compound (1.79 g, 95.4%).

Example 4-2 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with anoverhead stirrer was charged withtris(dibenzylideneacetone)dipalladium(0) (0.105 g, 0.115 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.133 g, 0.275 mmol) and milled potassium phosphate tribasic (5.35 g,25.2 mmol). The flask was purged with argon for not less than 90minutes. 2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL roundbottom flask, purged with argon for not less than 30 minutes and wastransferred to the 450-mL reactor using a cannula under argonatmosphere. The contents of the 450-mL reactor were heated to 80° C. andstirred at this temperature for 30 minutes. A 250-mL, round bottom flaskequipped with a magnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (16.0 g, 22.9 mmol),methanesulfonamide (2.61 g, 27.5 mmol) and 2-methyltetrahydrofuran (155mL), purged with argon for not less than 60 minutes. This solution wastransferred to the 450-mL reactor that has been cooled to the roomtemperature using a cannula under argon atmosphere. The temperature ofthe 450-mL flask was raised to 90° C. and the contents were stirred for14 hours. The reaction mixture was allowed to cool down to 70° C.,diluted with ethyl acetate (190 mL) and stirred for 3 hours at 70° C.,cooled to the room temperature, stirred for an additional 4 hours,filtered through a fine fit filter funnel and rinsed with ethyl acetate(90 mL) to obtain 29.4 g of light brown solid. A portion of this solid(13.04 g) was transferred to a 500-mL, 3-neck round bottom flaskequipped with an overhead stirrer and a thermocouple. Tetrahydrofuran(175 mL) was added, followed by the addition of water 50 mL containingL-cysteine (0.63 g) and sodium chloride (5.5 g). The reaction mixturewas stirred for 2 hours at 50° C. under a slight positive pressure ofargon. The reaction mixture was transferred to a 500-mL separatoryfunnel and the aqueous layer was discarded. The organic layer wasfiltered through an approximately 2-inch pad of diatomaceous earth andrinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellowsolution. The organic layer was concentrated to a total weight of 45.59g. A portion of this organic solution (41.58 g) was charged to a 250-mL,3-neck round bottom flask fitted with an overhead stirrer. Ethyl acetate(80 mL) was added over 6 hours by a pump with constant stirring at roomtemperature. The product was collected by filtration, rinsed with ethylacetate (20 mL) and dried in a vacuum oven for 2 hours to obtain 3.17 gof the title compound (>99.8 pure and 94.6% potent vs. standard).

Example 4-3 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 600-mL, stainless steel Parr® pressure reactor equipped with anoverhead stirrer was charged withtris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.251 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.291 g, 0.601 mmol) and milled potassium phosphate tribasic (11.70 g,55.1 mmol). The flask was purged with argon for not less than 90minutes. Ethyl acetate (140 mL) was taken in a 250-mL, round bottomflask, purged with argon for not less than 30 minutes and wastransferred to the 600-mL reactor using a cannula under argonatmosphere. The contents of the 600-mL reactor were heated to 80° C. andstirred at this temperature for 30 minutes. A 500-mL round bottom flaskequipped with a magnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (35.0 g, 50.1 mmol),methanesulfonamide (5.72 g, 60.1 mmol) and ethyl acetate (280 mL),purged with argon for not less than 60 minutes while stirring at 50° C.This solution was transferred to the 600-mL reactor that had been cooledto room temperature using a cannula under argon atmosphere. Thetemperature of the 600-mL flask was raised to 90° C., and the contentswere stirred for 18 hours. The reaction mixture was allowed to cool downto 40° C., filtered and rinsed with ethyl acetate (140 mL). Solid (41.50g) was obtained after drying for 2 hours on high vacuum. This solidcontained the titled product (23.06 g, 93%).

Example 4-4 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0066 g, 7.16 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0083 g, 17 μmol) and milled potassium phosphate tribasic (0.334 g,1.58 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. t-Amyl alcohol (4 mL) was added, the vial wascapped, and the contents were heated to 80° C. and stirred at thistemperature for 30 minutes. The reaction mixture was cooled down to theroom temperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 1.43 mmol),methanesulfonamide (0.163 g, 1.72 mmol) and t-amyl alcohol (8 mL) wereadded to the 40-mL reaction vial, and the vial was capped. The reactiontemperature was raised to 90° C. and the contents were stirred for 5hours. HPLC analysis of the reaction mixture showed that the product wasformed in 94 area % at 210 nm.

Example 4-5 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overheadstirrer, thermocouple and a heating mantle.Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.208 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g,39.4 mmol) were charged to the 600-mL reactor. The reactor was purgedwith argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100mL) was purged with argon for not less than 30 minutes and wastransferred to the 600-mL reactor using a cannula under argonatmosphere. The reactor was tightly sealed, the contents were heated to80° C. and stirred at this temperature for 30 minutes. A 500-mL roundbottom flask equipped with a magnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol),methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL),purged with argon for not less than 30 minutes with stirring and heatedto 60° C. A clear solution was observed. This solution was transferredto the 600-mL reactor using a cannula under argon atmosphere. Thereactor was tightly sealed, the contents were heated to 90° C. andstirred at this temperature for 14 hours. The reaction mixture wascooled to 35° C., solids were collected by filtration, washed with ethylacetate (300 mL) and dried under high vacuum for 2-4 hours. The solidswere then transferred to a 1-L, three-neck, round-bottom flask equippedwith an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid(0.85 g) were charged to the 1-L flask; the contents were heated to 60°C. and mixed for 1 hour. The mixture was filtered through approximately2-inch pad of diatomaceous earth and washed with DMF (50 mL). Thedark-brown/black-colored solid collected on diatomaceous earth wasdiscarded and the light yellow/clear filtrate was charged to a separate1-L, three-neck, round-bottom flask equipped with an overhead stirrer, athermocouple and a syringe pump. The DMF solution was mixed and methanol(300 mL) was added over 8 hours, while maintaining the internaltemperature at 25±5° C. The white solid was collected by filtrationwashed with methanol (150 mL) and dried in a vacuum oven at 50° C. fornot less than 8 hours. The title compound was isolated as a white solid(15.8 g, 89% yield).

Example 4-6 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overheadstirrer, thermocouple and a heating mantle.Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol),7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane(0.238 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g,39.4 mmol) were charged to the 600-mL reactor. The reactor was purgedwith argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100mL) was purged with argon for not less than 30 minutes and wastransferred to the 600-mL reactor using a cannula under argonatmosphere. The reactor was tightly sealed, the contents were heated to80° C. and stirred at this temperature for 30 minutes. A 500-mL roundbottom flask equipped with a magnetic stir bar was charged with6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol),methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL),purged with argon for not less than 30 minutes with stirring and heatedto 60° C. A clear solution was observed. This solution was transferredto the 600-mL reactor using a cannula under argon atmosphere. Thereactor was tightly sealed, the contents were heated to 90° C. andstirred at this temperature for 14 hours. The reaction mixture wascooled to 35° C., 5% aqueous N-acetyl-L-cysteine solution (100 mL) wasadded and the contents were mixed for 1 hour at 35° C. Solids werecollected by filtration, washed with water (2×25 mL) and ethyl acetate(3×80 mL) and were dried under high vacuum for 2-4 hours. The solidswere then transferred to a 1-L, three-neck, round-bottom flask equippedwith an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid(0.85 g) were charged to the 1-L flask; the contents were heated to 60°C. and mixed for 1 hour. The mixture was filtered through anapproximately 2-inch pad of diatomaceous earth and washed with DMF (50mL). The dark-brown/black-colored solid collected on the diatomaceousearth was discarded and the light yellow/clear filtrate was charged to aseparate 1-L, three-neck, round-bottom flask equipped with an overheadstirrer, a thermocouple and a syringe pump. The DMF solution was mixedand methanol (300 mL) was added over 8 hours, while maintaining theinternal temperature at 25±5° C. The white solid was collected byfiltration washed with methanol (150 mL) and dried in a vacuum oven at50° C. for not less than 8 hours. The title compound was isolated as awhite solid (15.6 g, 88% yield).

Example 4-7 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0026 g, 2.80 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0033 g, 6.72 μmol) and milled potassium phosphate tribasic (0.131 g,0.616 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. 2-Methyltetrahydrofuran (1.5 mL) was added, thevial was capped, and the contents were heated to 80° C. and stirred atthis temperature for 30 minutes. The reaction mixture was cooled down toroom temperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (0.4 g, 0.560mmol, Example 3-7, compound (5f)), methanesulfonamide (0.064 g, 0.672mmol) and ethyl acetate (3 mL) were added to the 40-mL reaction vial.The temperature of the closed vial was raised to 90° C. and the contentswere magnetically stirred for 16 hours. HPLC analysis of the reactionmixture showed that the product was formed in 97 area % at 210 nm.

Example 4-8 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0071 g, 7.71 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0089 g, 19.0 μmol) and milled potassium phosphate tribasic (0.360 g,1.696 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. 2-Methyltetrahydrofuran (4 mL) was added, and theclosed vial and its contents were heated to 80° C. with magneticstirring for 30 minutes. The reaction mixture was cooled down to roomtemperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (1.0 g, 1.542 mmol, Example3-4, compound (5c)), methanesulfonamide (0.176 g, 1.850 mmol) and ethylacetate (8 mL) were added to the 40-mL reaction vial. The temperature ofthe closed vial and its contents was raised to 90° C. and stirred for 20hours. HPLC analysis of the reaction mixture showed that the product wasformed in 95 area % at 210 nm.

Example 4-9 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0055 g, 6.02 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0070 g, 14.0 μmol) and milled potassium phosphate tribasic (0.281 g,1.324 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. 2-Methyltetrahydrofuran (3.4 mL) was added, andthe closed vial and its contents were heated to 80° C. with magneticstirring for 30 minutes. The reaction mixture was cooled down to roomtemperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylsulfofluoridate (0.6 g, 1.204 mmol, Example 3-8, compound (5g)),methanesulfonamide (0.137 g, 1.444 mmol) and ethyl acetate (6.7 mL) wereadded to the 40-mL reaction vial. The temperature of the closed reactionvial and its contents was raised to 90° C. and the contents were stirredfor 20 hours. HPLC analysis of the reaction mixture showed that theproduct was formed in 79 area % at 210 nm.

Example 4-10 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0042 g, 4.56 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0053 g, 12.0 μmol) and milled potassium phosphate tribasic (0.213 g,1.003 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. 2-Methyltetrahydrofuran (1.9 mL) was added, andthe closed vial and its contents were heated to 80° C. with magneticstirring for 30 minutes. The reaction mixture was cooled down to roomtemperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yltrifluoromethanesulfonate (0.5 g, 0.912 mmol, Example 3-6, compound(5e)), methanesulfonamide (0.104 g, 1.094 mmol) and ethyl acetate (5.7mL) were added to the 40-mL reaction vial. The temperature of the closedvial and its contents was raised to 90° C. and stirred for 14 hours.HPLC analysis of the reaction mixture showed that the product was formedin 91 area % at 210 nm.

Example 4-11 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0037 g, 4.04 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0047 g, 9.7 μmol) and milled potassium phosphate tribasic (0.094 g,0.445 mmol) were charged to a 40-mL reaction vial inside an inertatmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, the contentswere heated to 80° C. and stirred at this temperature for 30 minutes.The reaction mixture was cooled down to room temperature.6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylmethanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485mmol) and tert-amyl alcohol (1.5 mL) were added to a 40-mL reactionvial. The reaction temperature was raised to 110° C., and the contentswere stirred for 14 hours. HPLC analysis of the reaction mixture showedthat the titled compound was formed in 7 area % at 210 nm.

Example 4-12 Alternative Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

Palladium acetate (0.0018 g, 8.09 μmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine(0.0086 g, 0.018 mmol) and water (0.6 μL, 0.032 mmol) were charged to a40-mL reaction vial inside an inert atmosphere glove box. tert-Amylalcohol (1.0 mL) was added, and the contents were heated to 80° C. andstirred at this temperature for 15 minutes. The reaction mixture wascooled down to room temperature. Potassium phosphate tribasic (0.094 g,0.445 mmol),6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylmethanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485mmol) and tert-amyl alcohol (1.5 mL) were added to the 40-mL reactionvial. The reaction temperature was raised to 110° C., and the contentswere stirred for 14 hours. HPLC analysis of the reaction mixture showedthat the titled compound was formed in 5 area % at 210 nm.

Example 4-13 Filterability ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(Compound (A-1))

A filter pad was inserted in the leaf filter bottom, before attachingthe assembly to the filter body. The top assembly was attached andsealed. The system was leak tested at 5-10 psig nitrogen to ensure atight seal, the pressure was relieved, and the nitrogen line regulatorset to the desired pressure for the filtration test. The distance fromthe filter pad to a reference mark on the filter body was measured usinga tape measure. About 50 mL of the process solvent was charged to thefilter, and the system was inspected to check for leaks. The filter topassembly was then attached to the filter body, and sealed. The solventwas passed through the filter to pre-wet the pad. The outlet valve wasthen closed.

About 200-250 mL of the slurry sample to be tested was transferred intoa graduated cylinder. The graduated cylinder was weighed. A taredfiltrate flask (receiver) was placed on an electronic balance locatedbelow the filter to collect the filtrate. Collection of the data signalfrom the electronic balance was started. The test slurry was chargedinto the filter body using a funnel, and the top assembly re-attachedand sealed. The nitrogen pressure was checked, and re-adjusted to thetarget value, as necessary. The nitrogen inlet valve was opened topressurize the filter body, and then the bottom drain valve was openedto start flow of filtrate into the receiver.

The actual nitrogen pressure achieved during the test was recorded. Thefiltrate weight was recorded as a function of time of filtration by thedata collection system. The graduated cylinder was re-weighed todetermine the weight of slurry charged. Once filtrate flow had stopped,the filtrate weight was determined, as well as the filtrate volume. Thetop assembly was opened, and the distance from the reference point onthe filter body to the top of the solid wet cake was measured. Thisallowed calculation of the cake height by difference from the startingvalue. The filtrate density was calculated from the weight and volume offiltrate. (Alternatively, a tared 10 mL volumetric flask was filled tothe mark with filtrate, and the weight determined to calculate thefiltrate density). The slurry density was calculated from the weight andvolume of slurry charged. The solvent viscosity was estimated using thepure solvent values, or, for mixtures by mass fraction averaging of thepure component viscosities. The filtration data were analyzed byplotting (t/V) versus V where t is the time (s) of filtration, and V isthe volume of filtrate (m³ or ft³) collected up until time t. Thisallowed estimation of the filter cake resistance from the method outlinein Geankoplis, C. J. “Transport Processes and Unit Operations”, 3rd ed.,copyright 1993. P T R Prentice-Hall, Inc, Englewood Cliffs, N.J.,wherein the slope of the line on the (t/V) versus V plot isK _(p)/2 where K _(p) =μαC _(s)/(A ² ΔPg _(c)) where

-   -   μ=is the viscosity in Pa·s or (lb_(m)/ft·s)    -   α=is the specific cake resistance, m/kg or ft/lb_(m)    -   C_(s)=solids concentration, kg/m³ or lb_(m)/ft³    -   A=cross-sectional area, m² or ft²    -   ΔP=pressure drop, N/m² or (lb_(f)/ft²)    -   g_(c)=32.174 lb_(m) ft/(lb_(f)·s)

Cake Reaction Crude Pressure Resistance Permeability Source [FreeExperiment (psig) (ft/lb) (m²) Acid Crystal Form] 1 9 6.6 × 10⁹  2.3 ×10⁻¹³ 2-methyltetra- hydrofuran/ethyl acetate [ethyl acetate solvate] 25 4.6 × 10⁹  3.9 × 10⁻¹³ 2-methyltetra- hydrofuran/ethyl acetate [ethylacetate solvate] 3 10 6.0 × 10¹⁰ 4.4 × 10⁻¹⁴ 2-methyltetra- hydrofuran[anhydrate] 4 23 3.65 × 10¹⁰  5.4 × 10⁻¹⁴ 2-methyltetra- hydrofuran[anhydrate] 5 10 1.5 × 10¹¹ 2.3 × 10⁻¹⁴ t-amyl alcohol [anhydrate] CakeResistance Interpretation: 1 ft/lb = 0.67 kg/m 1.0 × 10⁹ ft/lb:moderately fast filtering 1.0 × 10¹⁰ ft/lb: slow but acceptablefiltering 1.0 × 10¹¹ ft/lb: very slow filtering 1.0 × 10¹² ft/lb:difficult to filter

As seen in the above table, reaction solvent mixtures in Experiments 1-4provided enhanced rates of filtration.

Example 5 Preparation of the Sodium Salt ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(compound (A-s1))

A solution of 2-propanol and water was prepared by combining 18.5 g ofwater and 512 g of 2-propanol. Hereafter, this solution is referred toas the “antisolvent solution.”

A solution of 2-propanol and water was prepared by combining 23.94 g ofwater and 564 g of 2-propanol. This solution was cooled in arefrigerator prior to use. Hereafter, this solution is referred to asthe “chilled wash solution.”

A jacketed reactor was equipped with an overhead stirrer and chargedwith 32.0 g (64.8 mmol) ofN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamideand 105.9 g of dimethyl sulfoxide. With stirring the mixture was heatedto an internal temperature of 68° C. A solution of 2.66 g of sodiumhydroxide (66.5 mmol, 1.026 equiv) in 16 g of water was added to thereactor over several minutes, followed by 12.4 g of 2-propanol whilemaintaining the internal temperature at 68° C. Antisolvent solution(24.5 g) was added to the reactor while maintaining the internaltemperature at 68° C. A slurry of 0.32 g of seed crystals of the finalproduct in 22.8 g of antisolvent solution was added to the reactor,followed by a 2.6 g rinse of the flask with antisolvent solution. Thereaction mixture was stirred for 1.5 hours while maintaining theinternal temperature at 68° C. Antisolvent solution (354 g) was added tothe reactor over 7 hours while maintaining the internal temperature at68° C. The contents of the reactor were cooled to an internaltemperature of 0° C. over 7 hours and then mixed at 0° C. for 7 hours.The solids were isolated by filtration and washed with 252 g of thechilled wash solution. The isolated solids were dried in a vacuum ovenat 50° C. for 19 hours. The title compound was isolated as a white solid(30.7 g, 92% potency vs. free acid standard, 57.2 mmol free acidequivalent, 88% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75 (s, 1H),7.72 (d, J=7.8 Hz, 1H), 7.59 (dd, J=8.8, 2.2 Hz, 2H), 7.45 (dd, J=8.5,1.8 Hz, 1H), 7.27 (d, J=2.6 Hz, 2H), 7.21 (d, J=2.7 Hz, 1H), 7.06 (dd,J=8.8, 2.2 Hz, 1H), 5.62 (d, J=7.8 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H),1.40 (s, 9H).

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize assertions made by theirauthors. No admission is made that any reference (or a portion of areference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

We claim:
 1. A process for preparing compounds of formula (A) or a salt thereof, wherein the process comprises: sulfonamidating compound (5) using a palladium catalyst or palladium catalyst precursor and phosphine ligand in the presence of a base and a solvent:

wherein LG¹ is a leaving group; R⁴ is selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-hydroxyalkyl, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, and 3-furanyl; R⁵ is selected from the group consisting of hydrogen, fluoro, chloro, C₁-C₆-alkyl, and C₁-C₆-alkyloxy; and R⁶ is selected from the group consisting of C₁-C₆-alkyl and C₁-C₆-fluoroalkyl.
 2. The process of claim 1, wherein LG¹ is selected from the group consisting of chloro, bromo, iodo and —OSO₂R^(1a), wherein R^(1a) is selected from the group consisting of aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl, —N(alkyl)₂, —O(alkyl), —O(aryl), fluoro, imidazolyl, and isomers and homologs thereof.
 3. The process of claim 1, wherein R⁴ is t-butyl, R⁵ is methoxy, and R⁶ is methyl.
 4. The process of claim 2, wherein R^(1a) is C₄F₉.
 5. The process of claim 2, wherein R^(1a) is perfluorobutyl or trifluoromethyl.
 6. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate.
 7. The process of claim 1, wherein the palladium catalyst or palladium catalyst precursor is selected from the group consisting of tetrakis(triphenylphosphine)palladium(0), dichlorobis(tri-o-tolylphosphine)palladium(II), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), dichlorobis(tricyclohexylphosphine) palladium(II), dichlorobis(triphenylphosphine) palladium(II), chloro(η3-allyl)palladium(II) dimer, palladium(II) chloride, palladium(II) bromide, and bis(acetonitrile)dichloropalladium(II).
 8. The process of claim 1, wherein the ligand is di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine, di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine or 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane.
 9. The process of claim 1, wherein the base is selected from the group consisting of potassium phosphate tribasic, cesium carbonate, potassium carbonate, sodium carbonate, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide.
 10. The process of claim 9, wherein the base is hydrated potassium phosphate tribasic.
 11. The process of claim 1, wherein the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, cyclopentyl methyl ether, toluene, benzene, tert-amyl alcohol, and tert-butyl alcohol or mixtures thereof.
 12. The process of claim 11, wherein the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, a mixture of 2-methyltetrahydrofuran and ethyl acetate and a mixture of tert-amyl alcohol and dimethyl sulfoxide.
 13. The process of claim 12, wherein the solvent is a 1:2 to 1:3 mixture of 2-methyltetrahydrofuran and ethyl acetate.
 14. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine to give compound (A).
 15. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 16. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinane to give compound (A).
 17. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane to give compound (A).
 18. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-ol to give compound (A).
 19. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 8-(2′,6′-diisopropoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 20. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 1,3,5,7-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^(3,7)]decane to give compound (A).
 21. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 8-(2′,6′-dimethoxybiphenyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 22. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 6-methoxy-N,N-dimethyl-2′-(7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decan-8-yl)biphenyl-2-amine to give compound (A).
 23. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 8-(2′-methoxy-1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 24. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 25. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 7,7,9,9-tetramethyl-8-(2-(naphthalen-1-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 26. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 7,7,9,9-tetramethyl-8-(2-(naphthalen-2-yl)phenyl)-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 27. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in tetrahydrofuran in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine to give compound (A).
 28. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in 2-methyltetrahydrofuran in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine to give compound (A).
 29. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in ethyl acetate in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine to give compound (A).
 30. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in t-amyl alcohol in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine to give compound (A).
 31. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in a mixture of 2-methyltetrahydrofuran and ethyl acetate in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine to give compound (A).
 32. The process of claim 1, wherein compound (5) is reacted with methanesulfonamide in a mixture of 2-methyltetrahydrofuran and ethyl acetate in the presence of potassium phosphate tribasic, tris(dibenzylideneacetone)dipalladium(0) and 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane to give compound (A).
 33. The process of claim 1 wherein compound (5) corresponds in structure to formula (5-I):


34. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,-heptafluoropropane-1-sulfonate.
 35. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate.
 36. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,2-pentafluoroethanesulfonate.
 37. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate.
 38. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate.
 39. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl sulfofluoridate.
 40. The process of claim 1 wherein compound (5) is 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate.
 41. The process of claim 2, wherein R^(1a) is selected from the group consisting of p-tolyl, phenyl, methyl, ethyl, fluoro, trifluoromethyl, pentafluoroethyl, 1-heptafluoropropyl, 2-heptafluoropropyl, perfluorobutyl, isomers of perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluorooctyl, and perfluoroethoxyethyl.
 42. The process of claim 1, wherein the solvent is a mixture of 2-methyltetrahydrofuran and ethyl acetate.
 43. The process of claim 42, wherein the solvent is a 1:2 mixture of 2-methyltetrahydrofuran and ethyl acetate.
 44. The process of claim 42, wherein the solvent is a 1:3 mixture of 2-methyltetrahydrofuran and ethyl acetate.
 45. The process of claim 1, wherein the solvent is a mixture of tert-amyl alcohol and dimethyl sulfoxide.
 46. The process of claim 45, wherein the solvent is a 7:1 mixture of tert-amyl alcohol and dimethyl sulfoxide.
 47. The process of claim 1, wherein the phosphine ligand has a structure corresponding to the structure of formula (I),

or a salt thereof, wherein Ar¹ and Ar² are each independently aryl or heteroaryl, and wherein Ar¹ and Ar² are each independently optionally substituted with one or more R¹ and R², respectively; R¹ and R² are independently selected at each occurrence from the group consisting of hydrogen; amino; hydroxyl; cyano; halo; alkyl; alkenyl; alkynyl; haloalkyl; haloalkoxy; oxoalkyl; alkoxy; alkylamino; dialkylamino; cycloalkyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; cycloalkyloxy optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; 5- or 6-membered heteroaryl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl or haloalkoxy; hydroxyalkyl; hydroxyalkoxy; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl; N,N,N-trialkylammoniumalkyl; L¹-C(O)—OR^(1′), L¹-P(O)—(OR^(1′))₂, or L¹-S(O)₂—OR^(1′), wherein L¹ is a bond or alkylene, and R^(1′) is selected from the group consisting of hydrogen, alkyl and hydroxyalkyl; L²-O—C(O)—R^(2′), wherein L² is a bond or alkylene, and R^(2′) is alkyl or hydroxyalkyl; L³-C(O)—NR^(3′)R^(4′), wherein L³ is a bond or alkylene, and R^(3′) and R^(4′) are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl; L⁴-NR^(5′)—C(O)—R^(6′), wherein L⁴ is a bond or alkylene, R^(5′) is hydrogen or alkyl, and R^(6′) is alkyl or hydroxyalkyl; sulfamoyl; N-(alkyl)sulfamoyl; N,N-(dialkyl)sulfamoyl; sulfonamide; sulfate; alkylthio; thioalkyl; and a ring containing an alkylene or —O—(CH₂)_(m)—O— formed by the joining together of any two R¹ or any two R² or an R¹ and an R², wherein m is 1, 2, 3 or 4; and X is a cyclic or acyclic phosphine.
 48. The process of claim 47, wherein X is an acyclic phosphine.
 49. The process of claim 48, wherein X is a dialkyl phosphine.
 50. The process of claim 49, wherein X is —P(t-butyl)₂.
 51. The process of claim 48, wherein the phosphine ligand is di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine.
 52. The process of claim 48, wherein the phosphine ligand is di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine.
 53. The process of claim 47, wherein X is a cyclic phosphine.
 54. The process of claim 47, wherein the phosphine ligand is 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane.
 55. The process of claim 47, wherein R¹ and R² are independently selected at each occurrence from the group consisting of hydrogen; alkyl; alkoxy; dialkylamino; haloalkyl; and phenyl.
 56. The process of any one of claims 47-55, wherein the palladium catalyst or palladium catalyst precursor is selected from the group consisting of tetrakis(triphenylphosphine)palladium(0), dichlorobis(tri-o-tolylphosphine)palladium(II), palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), dichlorobis(tricyclohexylphosphine) palladium(II), dichlorobis(triphenylphosphine) palladium(II), chloro(η3-allyl)palladium(II) dimer, palladium(II) chloride, palladium(II) bromide, and bis(acetonitrile)dichloropalladium(II). 